Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Ide Tomomi Last modified date:2019.06.17

Associate Professor / Faculty of Medical Sciences


Papers
1. Kisho Ohtani, Takeo Fujino, Tomomi Ide, Kouta Funakoshi, Ichirou Sakamoto, Hiasa Ken-Ichi, Taiki Higo, Kenjiro Kamezaki, Koichi Akashi, Hiroyuki Tsutsui, Recovery from left ventricular dysfunction was associated with the early introduction of heart failure medical treatment in cancer patients with anthracycline-induced cardiotoxicity, Clinical Research in Cardiology, 10.1007/s00392-018-1386-0, 108, 6, 600-611, 2019.06, Background: Left ventricular (LV) dysfunction due to anthracycline-induced cardiotoxicity (AIC) has been believed to be irreversible. However, this has not been confirmed and standard medical treatment for heart failure (HF) including renin–angiotensin inhibitors and β-blockers may lead to its recovery. Methods and results: We thus retrospectively studied 350 cancer patients receiving anthracycline-based chemotherapy from 2001 to 2015 in our institution. Fifty-two patients (14.9%) developed AIC with a decrease in LV ejection fraction (LVEF) of 24.1% at a median time of 6 months [interquartile range (IQR) 4–22 months] after anthracycline therapy. By multivariate analysis, AIC was independently associated with cardiac comorbidities including ischemic heart disease, valvular heart disease, arrhythmia, and cardiomyopathy [odds ratio (OR) 6.00; 95% confidence interval (CI) 2.27–15.84, P = 0.00044), lower baseline LVEF (OR per 1% 1.09; 95% CI 1.04–1.14, P = 0.00034). During the median follow-up of 3.2 years, LV systolic dysfunction recovered among 33 patients (67.3%) with a median time of 4 months (IQR 2–6 months), which was independently associated with the introduction of standard medical treatment for HF (OR 9.39; 95% CI 2.27–52.9, P = 0.0014) by multivariate analysis. Conclusion: Early initiation of standard medical treatment for HF may lead to LV functional recovery in AIC..
2. Tomomi Ide, Kisho Ohtani, Taiki Higo, Makoto Tanaka, Yasushi Kawasaki, Hiroyuki Tsutsui, Ivabradine for the treatment of cardiovascular diseases, Circulation Journal, 10.1253/circj.CJ-18-1184, 83, 2, 252-260, 2019.02, Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization- activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the If current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of If inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation..
3. Yasuki Nakada, Rika Kawakami, Shoji Matsushima, Tomomi Ide, Koshiro Kanaoka, Tomoya Ueda, Satomi Ishihara, Taku Nishida, Kenji Onoue, Tsunenari Soeda, Satoshi Okayama, Makoto Watanabe, Hiroyuki Okura, Miyuki Tsuchihashi-Makaya, Hiroyuki Tsutsui, Yoshihiko Saito, Simple risk score to predict survival in acute decompensated heart failure
A2B score, Circulation Journal, 10.1253/circj.CJ-18-1116, 83, 5, 1019-1024, 2019.01, Background: Prognosis after acute decompensated heart failure (ADHF) is poor. An appropriate risk score that would allow for improved care and treatment of ADHF patients after discharge, however, is lacking. Methods and Results: We used 2 HF cohorts, the NARA-HF study and JCARE-CARD, as derivation and validation cohorts, respectively. The primary endpoint was all-cause death during the 2-year follow-up, excluding in-hospital death. Age, hemoglobin (Hb), and brain natriuretic peptide (BNP) at discharge were identified as independent risk factors. We determined 3 categorizations on the basis of these parameters, termed A2B score: age (<65 years, 0; 65-74 years, 1; ≥75 years, 2), anemia (Hb <10 g/dL, 2; 10-11.9 g/dL, 1; ≥12 g/dL, 0) and BNP (<200 pg/mL, 0; 200-499 pg/mL, 1; ≥500 pg/mL, 2). We divided patients into 4 groups according to A2B score (extremely low, 0; low, 1-2; medium, 3-4; high, 5-6). For the extremely low-risk group, the 2-year survival rate was 97.8%, compared with 84.5%, 66.1%, and 45.2% for the low-, medium-, and high-risk groups, respectively. Using the JCARE-CARD as a validation model, for the extremely low-risk group, the 2-year survival was 95.4%, compared with 90.2%, 75.0%, and 55.6% for the low-, medium-, and high-risk groups, respectively. Conclusions: The user-friendly A2B score is useful for estimating survival rate in ADHF patients at discharge..
4. Mari Sakamoto, Hiroki Fukuda, Jiyoong Kim, Tomomi Ide, Shintaro Kinugawa, Arata Fukushima, Hiroyuki Tsutsui, Akira Ishii, Shin Ito, Hiroshi Asanuma, Masanori Asakura, Takashi Washio, Masafumi Kitakaze, The impact of creating mathematical formula to predict cardiovascular events in patients with heart failure, Scientific reports, 10.1038/s41598-018-22347-0, 8, 1, 2018.12, Since our retrospective study has formed a mathematical formula, α = f(x
1
, .., x
252
), where α is the probability of cardiovascular events in patients with heart failure (HF) and x
1
is each clinical parameter, we prospectively tested the predictive capability and feasibility of the mathematical formula of cardiovascular events in HF patients. First of all, to create such a mathematical formula using limited number of the parameters to predict the cardiovascular events in HF patients, we retrospectively determined f(x) that formulates the relationship between the most influential 50 clinical parameters (x) among 252 parameters using 167 patients hospitalized due to acute HF; the nonlinear optimization could provide the formula of α = f(x
1
, .., x
50
) which fitted the probability of the actual cardiovascular events per day. Secondly, we prospectively examined the predictability of f(x) in other 213 patients using 50 clinical parameters in 3 hospitals, and we found that the Kaplan-Meier curves using actual and estimated occurrence probabilities of cardiovascular events were closely correlated. We conclude that we created a mathematical formula f(x) that precisely predicted the occurrence probability of future cardiovascular outcomes of HF patients per day. Mathematical modelling may predict the occurrence probability of cardiovascular events in HF patients..
5. Akiyuki Nishimura, Tsukasa Shimauchi, Tomohiro Tanaka, Kakeru Shimoda, Takashi Toyama, Naoyuki Kitajima, Tatsuya Ishikawa, Naoya Shindo, Takuro Numaga-Tomita, Satoshi Yasuda, Yoji Sato, Koichiro Kuwahara, Yoshito Kumagai, Takaaki Akaike, Tomomi Ide, Akio Ojida, Yasuo Mori, Motohiro Nishida, Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence, Science Signaling, 10.1126/scisignal.aat5185, 11, 556, 2018.11, Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission-associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hyperfission and associated with myocardial senescence, filamin A colocalized with Drp1 around mitochondria. Hypoxic stress induced the interaction of filamin A with the GTPase domain of Drp1 and increased Drp1 activity in an actin-binding-dependent manner in rat cardiomyocytes. Expression of the A1545T filamin mutant, which potentiates actin aggregation, promoted mitochondrial hyperfission under normoxia. Furthermore, pharmacological perturbation of the Drp1-filamin A interaction by cilnidipine suppressed mitochondrial hyperfission-associated myocardial senescence and heart failure after MI. Together, these data demonstrate that Drp1 association with filamin and the actin cytoskeleton contributes to cardiac fragility after MI and suggests a potential repurposing of cilnidipine, as well as provides a starting point for innovative Drp1 inhibitor development..
6. Chiharu Ishii, Takeyuki Akita, Masashi Mita, Tomomi Ide, Kenji Hamase, Development of an online two-dimensional high-performance liquid chromatographic system in combination with tandem mass spectrometric detection for enantiomeric analysis of free amino acids in human physiological fluid, Journal of Chromatography A, 10.1016/j.chroma.2018.07.076, 1570, 91-98, 2018.10, An automated two-dimensional HPLC-MS/MS system was designed and developed for the highly selective determination of trace levels of D-amino acids. As the targets, frequently observed ones in mammalian physiological fluids, Ala, Asp, Glu, Leu, Pro and Ser, were selected because these D-amino acids are the potential biomarkers for the early and sensitive diagnoses of various diseases. The target analytes were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), then isolated by a reversed-phase column in the first dimension. The NBD-amino acid fractions were automatically collected into the multi-loop device, and introduced into the enantioselective column in the second dimension to separate the D- and L-forms followed by detection by an MS/MS. The obtained resolution values of the enantiomers were 1.87–5.17 and the calibration lines, precision and accuracy were practically sufficient. By using the present 2D HPLC-MS/MS system, trace levels of D-amino acids in complex biological matrices were determined without disturbance by the intrinsic interfering compounds, and successfully applied to the analysis of the human clinical samples (plasma and urine)..
7. Hiroki Fukuda, Kazuhiro Shindo, Mari Sakamoto, Tomomi Ide, Shintaro Kinugawa, Arata Fukushima, Hiroyuki Tsutsui, Shin Ito, Akira Ishii, Takashi Washio, Masafumi Kitakaze, Elucidation of the Strongest Predictors of Cardiovascular Events in Patients with Heart Failure, EBioMedicine, 10.1016/j.ebiom.2018.06.001, 33, 185-195, 2018.07, Background: In previous retrospective studies, we identified the 50 most influential clinical predictors of cardiovascular outcomes in patients with heart failure (HF). The present study aimed to use the novel limitless-arity multiple-testing procedure to filter these 50 clinical factors and thus yield combinations of no more than four factors that could potentially predict the onset of cardiovascular events. A Kaplan–Meier analysis was used to investigate the importance of the combinations. Methods: In a multi-centre observational trial, we prospectively enrolled 213 patients with HF who were hospitalized because of exacerbation, discharged according to HF treatment guidelines and observed to monitor cardiovascular events. After the observation period, we stratified patients according to whether they experienced cardiovascular events (rehospitalisation or cardiovascular death). Findings: Among 77,562 combinations of fewer than five clinical parameters, we identified 151 combinations that could potentially explain the occurrence of cardiovascular events. Of these, 145 combinations included the use of inotropic agents, whereas the remaining 6 included the use of diuretics without bradycardia or tachycardia, suggesting that the high probability of cardiovascular events is exclusively determined by these two clinical factors. Importantly, Kaplan–Meier curves demonstrated that the use of inotropes or of diuretics without bradycardia or tachycardia were independent predictors of a markedly worse cardiovascular prognosis. Interpretation: Patients treated with either inotropic agents or diuretics without bradycardia or tachycardia were at a higher risk of cardiovascular events. The uses of these drugs, regardless of heart rate, are the strongest clinical predictors of cardiovascular events in patients with HF..
8. Chin Ling Hsieh, Reiko Koga, Aogu Furusho, Takeyuki Akita, Masashi Mita, Tomomi Ide, Jen Ai Lee, Kenji Hamase, Enantioselective and simultaneous determination of lactate and 3-hydroxybutyrate in human plasma and urine using a narrow-bore online two-dimensional high-performance liquid chromatography system, Journal of Separation Science, 10.1002/jssc.201701283, 41, 6, 1298-1306, 2018.03, For the enantioselective and simultaneous analysis of lactate and 3-hydroxybutyrate, a validated online two-dimensional high-performance liquid chromatography system using 4-nitro-7-piperazino-2,1,3-benzoxadiazole as a fluorescent derivatization reagent has been developed. For the reversed-phase separation in the first dimension, a Capcell Pak C18 ACR column (1.5 × 250 mm, particle size 3 μm) was used, and the target fractions were isolated by their hydrophobicity. In the second dimension, a polysaccharide-coated enantioselective column, Chiralpak AD-H (2.0 × 250 mm, 5 μm), was used. The system was validated by the calibration curve, intraday precision, interday precision, and accuracy using standards and real human samples, and satisfactory results were obtained. The present method was applied to human plasma and urine, and in the plasma, trace amounts of d-lactate (8.4 μM) and l-3-hydroxybutyrate (1.0 μM), besides high levels of l-lactate (860.9 μM) and d-3-hydroxybutyrate (59.4 μM), were successfully determined. In urine, trace levels of d-lactate (3.7 μM), d-3-hydroxybutyrate (2.3 μM), and l-3-hydroxybutyrate (3.3 μM) in addition to a relatively large amount of l-lactate (15.4 μM) were observed. The present online two-dimensional high-performance liquid chromatography system is useful for the simultaneous determination of all the lactate and 3-hydroxybutyrate enantiomers in human physiological fluids, and further clinical applications are ongoing..
9. Takeo Fujino, Shujiro Inoue, Shunsuke Katsuki, Taiki Higo, Tomomi Ide, Yoshinao Oda, Hiroyuki Tsutsui, Fatal cardiac hemochromatosis in a patient with hereditary spherocytosis, International heart journal, 10.1536/ihj.17-160, 59, 2, 427-430, 2018.01, A 31-year-old man was admitted to our hospital with atrial tachycardia and cardiogenic shock. He had been diagnosed with hereditary spherocytosis (HS) during childhood, but he never received any red blood cell transfusions. Right ventricular endomyocardial biopsy revealed multiple myocardial hemosiderin deposits, and he was diagnosed with cardiac hemochromatosis. In addition to the iron deposition in the heart, the loss of myocyte and severe interstitial fibrosis were present. His cardiac function did not improve even after the cardioversion for atrial tachycardia, and he suffered from recurrent heart failure. Despite intensive medical treatment for heart failure and arrhythmias in combination with iron chelation therapy, he eventually died of progressive and refractory heart failure. Hemochromatosis is a systemic disorder characterized by the excessive deposition of iron in multiple organs. The occurrence of hemochromatosis in HS is extremely rare, and previous reports have shown that the coexistence of heterozygosity for the HFE gene mutation in HS patients causes excess iron storage. The prognosis is poor due to progressive congestive heart failure and refractory arrhythmias. Here we report a rare case of fatal cardiac hemochromatosis associated with HS. The possibility of cardiac hemochromatosis needs to be considered in cases of heart failure or arrhythmia in patients with HS..
10. Akiko Nishizaki, Kisho Ohtani, Yuji Maehata, Motohiro Esaki, Tomomi Ide, Refractory coronary artery spasm associated with tacrolimus, Coronary Artery Disease, 10.1097/MCA.0000000000000538, 29, 1, 83-85, 2018.01.
11. Takuya Nishikawa, Keita Saku, Koji Todaka, Yukimitsu Kuwabara, Shinobu Arai, Takuya Kishi, Tomomi Ide, Hiroyuki Tsutsui, Kenji Sunagawa, The challenge of magnetic vagal nerve stimulation for myocardial infarction -preliminary clinical trial, 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2017 2017 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society Smarter Technology for a Healthier World, EMBC 2017 - Proceedings, 10.1109/EMBC.2017.8037812, 4321-4324, 2017.09, Numerous studies have shown in animal models that vagal nerve stimulation (VNS) strikingly reduces infarct size of acute myocardial infarction (AMI) and prevents heart failure. However, the lack of techniques to noninvasively stimulate the vagal nerve hinders VNS from clinical applications. Transcranial magnetic stimulation is noninvasive and capable of stimulating central neurons in patients. In this study, we examined whether the magnetic stimulation could noninvasively activate the cervical vagal nerve in healthy human. Sixteen healthy males and 4 females were enrolled in this study. We used Magstim Rapid2 with a 70-mm double coil in the right neck. We randomly assigned the subjects to 5 Hz or 20 Hz stimulation. We defined the maximum intensity of stimulation (MAX) which is the intensity just below the threshold of adverse effects. We defined HALF as a half of MAX. Protocols comprised 2 sets of MAX and 2 sets of HALF. Each stimulation continued for 3 minutes. We monitored heart rate (HR) and assessed the bradycardic response as an index of successful VNS. Nineteen subjects completed all protocols. They had no problematic adverse events during and/or after magnetic VNS. The magnetic VNS induced transient bradycardic responses in some subjects, whereas failed to induce sustained bradycardia in pooled data in any settings. Arterial pressure did not change either. Successful magnetic stimulation requires technical improvements including narrowing the magnetic focus and optimization of stimulation site. These improvements may enable us to apply magnetic VNS in the management of AMI..
12. Yoshiko Kuribayashi, Kisho Ohtani, Tsunenori Saito, Tomomi Ide, Electron microscopy gain a glimpse into the pathogenesis of cardiac sarcoidosis, European Heart Journal Cardiovascular Imaging, 10.1093/ehjci/jex152, 18, 8, 2017.08.
13. Tsukasa Shimauchi, Takuro Numaga-Tomita, Tomoya Ito, Akiyuki Nishimura, Ryosuke Matsukane, Sayaka Oda, Sumio Hoka, Tomomi Ide, Norimichi Koitabashi, Koji Uchida, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida, TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy, JCI insight, 10.1172/jci.insight.93358, 2, 15, 2017.08, Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress-mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load-induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy..
14. Takuya Nishikawa, Keita Saku, Koji Todaka, Yukimitsu Kuwabara, Shinobu Arai, Takuya Kishi, Tomomi Ide, Hiroyuki Tsutsui, Kenji Sunagawa, The challenge of magnetic vagal nerve stimulation for myocardial infarction -preliminary clinical trial, Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings, 10.1109/EMBC.2017.8037812, 2017, 4321-4324, 2017.07, Numerous studies have shown in animal models that vagal nerve stimulation (VNS) strikingly reduces infarct size of acute myocardial infarction (AMI) and prevents heart failure. However, the lack of techniques to noninvasively stimulate the vagal nerve hinders VNS from clinical applications. Transcranial magnetic stimulation is noninvasive and capable of stimulating central neurons in patients. In this study, we examined whether the magnetic stimulation could noninvasively activate the cervical vagal nerve in healthy human. Sixteen healthy males and 4 females were enrolled in this study. We used Magstim Rapid2 with a 70-mm double coil in the right neck. We randomly assigned the subjects to 5 Hz or 20 Hz stimulation. We defined the maximum intensity of stimulation (MAX) which is the intensity just below the threshold of adverse effects. We defined HALF as a half of MAX. Protocols comprised 2 sets of MAX and 2 sets of HALF. Each stimulation continued for 3 minutes. We monitored heart rate (HR) and assessed the bradycardic response as an index of successful VNS. Nineteen subjects completed all protocols. They had no problematic adverse events during and/or after magnetic VNS. The magnetic VNS induced transient bradycardic responses in some subjects, whereas failed to induce sustained bradycardia in pooled data in any settings. Arterial pressure did not change either. Successful magnetic stimulation requires technical improvements including narrowing the magnetic focus and optimization of stimulation site. These improvements may enable us to apply magnetic VNS in the management of AMI..
15. Michinobu Nagao, Yuzo Yamasaki, Satoshi Kawanami, Takeshi Kamitani, Koji Sagiyama, Taiki Higo, Tomomi Ide, Atsushi Takemura, Umiko Ishizaki, Kenji Fukushima, Yuji Watanabe, Hiroshi Honda, Quantification of myocardial oxygenation in heart failure using blood-oxygen-level-dependent T2* magnetic resonance imaging
Comparison with cardiopulmonary exercise test, Magnetic Resonance Imaging, 10.1016/j.mri.2017.02.005, 39, 138-143, 2017.06, Purpose Quantification of myocardial oxygenation (MO) in heart failure (HF) has been less than satisfactory. This has necessitated the use of invasive techniques to measure MO directly or to determine the oxygen demand during exercise using the cardiopulmonary exercise (CPX) test. We propose a new quantification method for MO using blood-oxygen-level-dependent (BOLD) myocardial T2* magnetic resonance imaging (M-T2* MRI), and investigate its correlation with CPX results. Methods Thirty patients with refractory HF who underwent cardiac MRI and CPX test for heart transplantation, and 24 healthy, age-matched volunteers as controls were enrolled. M-T2* imaging was performed using a 3-Tesla and multi-echo gradient-echo sequence. M-T2* was calculated by fitting the signal intensity data for the mid-left ventricular septum to a decay curve. M-T2* was measured under room-air (T2*-air) and after inhalation of oxygen for 10 min at a flow rate of 10 L/min (T2*-oxy). MO was defined as the difference between the two values (ΔT2*). Changes in M-T2* at the two conditions and ΔT2* between the two groups were compared. Correlation between ΔT2* and CPX results was analyzed using the Pearson coefficient. Results T2*-oxy was significantly greater than T2*-air in patients with HF (29.9 ± 7.3 ms vs. 26.7 ± 6.0 ms, p < 0.001), whereas no such difference was observed in controls (25.5 ± 4.0 ms vs. 25.4 ± 4.4 ms). ΔT2* was significantly greater for patients with HF than for controls (3.2 ± 4.5 ms vs. -0.1 ± 1.3 ms, p < 0.001). A significant correlation between ΔT2* and CPX results (peak VO2, r = − 0.46, p < 0.05; O2 pulse, r = − 0.54, p < 0.005) was observed. Conclusion ΔT2* is increased T2*-oxy is greater in patients with HF, and is correlated with oxygen metabolism during exercise as measured by the CPX test. Hence, ΔT2* can be used as a surrogate marker of MO instead of CPX test..
16. Kana Fujii, Keita Saku, Takuya Kishi, Yasuhiro Oga, Takeshi Tohyama, Takuya Nishikawa, takafumi sakamoto, Masataka Ikeda, Tomomi Ide, Hiroyuki Tsutsui, Kenji Sunagawa, Carotid body denervation markedly improves survival in rats with hypertensive heart failure, American Journal of Hypertension, 10.1093/ajh/hpx062, 30, 8, 791-798, 2017.01, BACKGROUND Hypertension is a major cause of heart failure. Excessive sympathoexcitation in patients with heart failure leads to poor prognosis. Since carotid body denervation (CBD) has been shown to reduce sympathetic nerve activity in animal models of hypertension and heart failure, we examined if bilateral CBD attenuates the progression of hypertensive heart failure and improves survival. METHODS We randomly allocated Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age into CBD (n = 31) and sham-operation (SHAM; n = 50) groups, and conducted CBD or SHAM at 7 weeks of age. We examined the time course of 24-hour urinary norepinephrine (uNE) excretion, blood pressure (BP) and the percent fractional shortening assessed by echocardiography, and estimated the pressure-natriuresis relationship at 14 weeks of age. Finally, we assessed hemodynamics, histological findings, and survival at 16 weeks of age. RESULTS Compared to SHAM, CBD significantly reduced 24-hour uNE at 12, 14, and 16 weeks of age, shifted the pressure-natriuresis relationship leftward without changing its slope, and attenuated the increase in BP. CBD preserved percent fractional shortening (34.2 ± 1.2 vs. 29.1 ± 1.3%, P < 0.01) and lowered left ventricular end-diastolic pressure (5.0 ± 0.9 vs. 9.0 ± 1.4 mm Hg, P < 0.05). Furthermore, CBD significantly attenuated myocardial hypertrophy (P < 0.01) and fibrosis (P < 0.01). Consequently, CBD markedly improved survival (relative risk reduction: 64.8%). CONCLUSIONS CBD attenuated the progression of hypertension and worsening of heart failure possibly through sympathoinhibition, and markedly improved survival in a rat model of hypertensive heart failure..
17. Shinobu Arai, Masataka Ikeda, Tomomi Ide, Yuka Matsuo, Takeo Fujino, Katsuya Hirano, Kenji Sunagawa, Hiroyuki Tsutsui, Functional loss of DHRS7C induces intracellular ca2+ overload and myotube enlargement in C2C12 cells via calpain activation, American Journal of Physiology - Cell Physiology, 10.1152/ajpcell.00090.2016, 312, 1, C29-C39, 2017.01, Dehydrogenase/reductase member 7C (DHRS7C) is a newly identified NAD/NADHdependent dehydrogenase that is expressed in cardiac and skeletal muscle and localized in the endoplasmic/sarcoplasmic reticulum (ER/ SR). However, its functional role in muscle cells remains to be fully elucidated. Here, we investigated the role of DHRS7C by analyzing mouse C2C12 myoblasts deficient in DHRS7C (DHRS7C-KO cells), overexpressing wild-type DHRS7C (DHRS7C-WT cells), or expressing mutant DHRS7C [DHRS7C-Y191F or DHRS7C-K195Q cells, harboring point mutations in the NAD/NADH-dependent dehydrogenase catalytic core domain (YXXXK)]. DHRS7C expression was induced as C2C12 myoblasts differentiated into mature myotubes, whereas DHRS7C-KO myotubes exhibited enlarged cellular morphology after differentiation. Notably, both DHRS7C-Y191F and DHRS7C-K195Q cells also showed similar enlarged cellular morphology, suggesting that the NAD/NADH-dependent dehydrogenase catalytic core domain is pivotal for DHRS7C function. In DHRS7CKO, DHRS7C-Y191F, and DHRS7C-K195Q cells, the resting level of cytosolic Ca2+ and total amount of Ca2+ storage in the ER/SR were significantly higher than those in control C2C12 and DHRS7C-WT cells after differentiation. Additionally, Ca2+ release from the ER/SR induced by thapsigargin and 4-chloro-m-cresol was augmented in these cells and calpain, a calcium-dependent protease, was significantly activated in DHRS7C-KO, DHRS7C-Y191F, and DHRS7C-K195Q myotubes, consistent with the higher resting level of cytosolic Ca2+ concentration and enlarged morphology after differentiation. Furthermore, treatment with a calpain inhibitor abolished the enlarged cellular morphology. Taken together, our findings suggested that DHRS7C maintains intracellular Ca2+ homeostasis involving the ER/SR and that functional loss of DHRS7C leads to Ca2+ overload in the cytosol and ER/SR, resulting in enlarged cellular morphology via calpain activation..
18. Takahiro Arimura, Keita Saku, Takamori Kakino, Takuya Nishikawa, Takeshi Tohyama, takafumi sakamoto, Kazuo Sakamoto, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Intravenous electrical vagal nerve stimulation prior to coronary reperfusion in a canine ischemia-reperfusion model markedly reduces infarct size and prevents subsequent heart failure, International Journal of Cardiology, 10.1016/j.ijcard.2016.10.074, 227, 704-710, 2017.01, Background Reducing myocardial damage is a prerequisite to prevent chronic heart failure after acute myocardial infarction (AMI). Although vagal nerve stimulation (VNS) has been repeatedly demonstrated to have potent anti-infarct effect, technical difficulties have precluded its clinical application. We developed a novel therapeutic strategy of intravenous VNS (iVNS) and examined whether iVNS administered prior to coronary reperfusion in a canine AMI model reduces infarct size and prevents heart failure. Methods and results In 35 mongrel dogs, we induced ischemia by ligating the left anterior descending coronary artery and then reperfused 3 h later (I/R). We transvenously placed a catheter electrode in the superior vena cava and adjusted the stimulation intensity to a level that induced bradycardia but maintained stable hemodynamics (continuous, 5.1 ± 2.1 V, 10 Hz). We administered iVNS from onset (iVNS-0, n = 7) or 90 min after onset (iVNS-90, n = 7) of ischemia until one hour after reperfusion. Four weeks after ischemia–reperfusion, iVNS markedly reduced infarct size (iVNS-0: 2.4 ± 2.1%, p < 0.05 and iVNS-90: 4.5 ± 4.5%, p < 0.05) compared with I/R control (I/R: 13.3 ± 2.5%), and improved cardiac performance and hemodynamics. Atrial pacing (n = 7) to abolish iVNS-induced bradycardia significantly attenuated the beneficial effects of iVNS. Conclusions Short-term iVNS delivered prior to coronary reperfusion markedly reduced infarct size and preserved cardiac function one month after AMI. The bradycardic effect plays an important role in the beneficial effect of iVNS. How other mechanisms contribute to the reduction of infarct size remains to be studied..
19. Takamori Kakino, Keita Saku, takafumi sakamoto, Kazuo Sakamoto, Takuya Akashi, Masataka Ikeda, Tomomi Ide, Takuya Kishi, Hiroyuki Tsutsui, Kenji Sunagawa, Prediction of hemodynamics under left ventricular assist device, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00617.2016, 312, 1, H80-H88, 2017.01, Left ventricular assist device (LVAD) saves lives in patients with severe left ventricular (LV) failure. However, predicting how much LVAD boosts total cardiac output (CO) remains difficult. This study aimed to develop a framework to quantitatively predict the impact of LVAD on hemodynamics. We adopted the circulatory equilibrium framework and incorporated LVAD into the integrated CO curve to derive the circulatory equilibrium. In anesthetized dogs, we ligated left coronary arteries to create LV failure and inserted a centrifugal pump as LVAD. Using CO and right (PRA) and left atrial pressure (PLA) measured before LVAD support, we predetermined the stressed volume (V) and logarithmic slope of right heart CO curve (SR). Next, we initiated LVAD at maximum level and then decreased LVAD flow stepwise while monitoring hemodynamic changes. We predicted LVAD-induced CO and PRA for given PLA from the predetermined SR and V and compared with those measured experimentally. The predicted CO [r2 = 0.907, SE of estimate (SEE) = 5.59 ml·min-1·kg-1, P < 0.001] and PRA (r2 = 0.967, SEE = 0.307 mmHg, P < 0.001) matched well with measured values indicating the validity of the proposed framework. We further conducted simulation using the validated framework to analyze the impact of LVAD on PRA under various right ventricular (RV) functions. It indicated that PRA is relatively insensitive to changes in RV end-systolic elastance or pulmonary arterial resistance, but sensitive to changes in V. In conclusion, the circulatory equilibrium framework predicts quantitatively the hemodynamic impact of LVAD. This knowledge would contribute to safe management of patients with LV failure undergoing LVAD implantation. NEW & NOTEWORTHY Hemodynamic response to left ventricular assist device (LVAD) has not been quantitatively investigated. This is the first report of quantitative prediction of the hemodynamics on LVAD using circulatory equilibrium framework. The validated framework allows us to simulate the impact of LVAD on right atrial pressure under various right ventricular functions..
20. Takuro Numaga-Tomita, Naoyuki Kitajima, Takuya Kuroda, Akiyuki Nishimura, Kei Miyano, Satoshi Yasuda, Koichiro Kuwahara, Yoji Sato, Tomomi Ide, Lutz Birnbaumer, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida, TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis, Scientific reports, 10.1038/srep39383, 6, 2016.12, Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca 2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca 2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca 2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule-Associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3-mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF) β stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubule-Associated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch-induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule-localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation..
21. Sugako Oka, Julio Leon, Sakumi Kunihiko, Tomomi Ide, Dongchon Kang, Frank M. LaFerla, Yusaku Nakabeppu, Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease, Scientific reports, 10.1038/srep37889, 6, 2016.11, In the mitochondria-mediated vicious cycle of Alzheimer's disease (AD), intracellular amyloid β (Aβ) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Aβ accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA). Expression of hTFAM significantly improved cognitive function, reducing accumulation of both 8-oxoguanine, an oxidized form of guanine, in mtDNA and intracellular Aβ in 3xTg-AD mice and increasing expression of transthyretin, known to inhibit Aβ aggregation. Next, we found that AD model neurons derived from human induced pluripotent stem cells carrying a mutant PSEN1 (P117L) gene, exhibited mitochondrial dysfunction, accumulation of 8-oxoguanine and single-strand breaks in mtDNA, and impaired neuritogenesis with a decreased expression of transthyretin, which is known to be downregulated by oxidative stress. Extracellular treatment with recombinant hTFAM effectively suppressed these deleterious outcomes. Moreover, the treatment increased expression of transthyretin, accompanied by reduction of intracellular Aβ. These results provide new insights into potential novel therapeutic targets..
22. Naoyuki Kitajima, Takuro Numaga-Tomita, Masahiko Watanabe, Takuya Kuroda, Akiyuki Nishimura, Kei Miyano, Satoshi Yasuda, Koichiro Kuwahara, Yoji Sato, Tomomi Ide, Lutz Birnbaumer, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida, TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling, Scientific reports, 10.1038/srep37001, 6, 2016.11, Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca 2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca 2+-dependent Nox2 activation through TRPC3-mediated background Ca 2+ entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca 2+ influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca 2+ influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities..
23. Takahiro Inoue, Masataka Ikeda, Tomomi Ide, Takeo Fujino, Yuka Matsuo, Shinobu Arai, Keita Saku, Kenji Sunagawa, Twinkle overexpression prevents cardiac rupture after myocardial infarction by alleviating impaired mitochondrial biogenesis, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00044.2016, 311, 3, H509-H519, 2016.09, Cardiac rupture is a fatal complication after myocardial infarction (MI). However, the detailed mechanism underlying cardiac rupture after MI remains to be fully elucidated. In this study, we investigated the role of mitochondrial DNA (mtDNA) and mitochondria in the pathophysiology of cardiac rupture by analyzing Twinkle helicase overexpression mice (TW mice). Twinkle overexpression increased mtDNA copy number approximately twofold and ameliorated ischemic cardiomyopathy at day 28 after MI. Notably, Twinkle overexpression markedly prevented cardiac rupture and improved post-MI survival, accompanied by the suppression of MMP-2 and MMP-9 in the MI border area at day 5 after MI when cardiac rupture frequently occurs. Additionally, these cardioprotective effects of Twinkle overexpression were abolished in transgenic mice overexpressing mutant Twinkle with an in-frame duplication of amino acids 353–365, which resulted in no increases in mtDNA copy number. Furthermore, although apoptosis and oxidative stress were induced and mitochondria were damaged in the border area, these injuries were improved in TW mice. Further analysis revealed that mitochondrial biogenesis, including mtDNA copy number, transcription, and translation, was severely impaired in the border area at day 5. In contrast, Twinkle overexpression maintained mtDNA copy number and restored the impaired transcription and translation of mtDNA in the border area. These results demonstrated that Twinkle overexpression alleviated impaired mitochondrial biogenesis in the border area through maintained mtDNA copy number and thereby prevented cardiac rupture accompanied by the reduction of apoptosis and oxidative stress, and suppression of MMP activity..
24. Akiko Nishizaki, Kazuo Sakamoto, Keita Saku, Kazuya Hosokawa, takafumi sakamoto, Yasuhiro Oga, Takuya Akashi, Yoshinori Murayama, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Optimal Titration Is Important to Maximize the Beneficial Effects of Vagal Nerve Stimulation in Chronic Heart Failure, Journal of Cardiac Failure, 10.1016/j.cardfail.2016.04.021, 22, 8, 631-638, 2016.08, Background Although vagal nerve stimulation (VNS) benefits patients with chronic heart failure (CHF), the optimal dose of VNS remains unknown. In clinical trials, adverse symptoms limited up-titration. In this study, we evaluated the impact of various voltages of VNS which were titrated below symptom threshold on cardiac function and CHF parameters in rat myocardial infarction (MI) models. Methods and Results We randomly allocated MI rats to vagal (VNS; n = 41) and sham (Sham; n = 16) stimulation groups. We stimulated the right vagal nerve with 20 Hz at 3 different voltages for 4 weeks. We defined Max as the highest voltage that did not evoke any symptom, Half as one-half of Max, and Quarter as one-fourth of Max. All 3 VNS groups significantly reduced biventricular weight compared with Sham (P < .05). In contrast, only Half decreased left ventricular (LV) end-diastolic pressure (Half: 17.5 ± 2.0 mm Hg; Sham: 24.2 ± 1.2 mm Hg; P < .05) and increased LV ejection fraction (Half: 37.9 ± 3.1%; Sham: 28.4 ± 2.3%,-P < .05) and LV maximum +dP/dt (Half: 5918.6 ± 2.0 mm/Hg/s; Sham: 5001.2 ± 563.2 mm Hg/s; P < .05). The number of large vagal nerve fibers was reduced with Max (Max: 163.1 ± 43.0 counts/bundle; Sham: 360.0 ±61.6 counts/bundle; P < .05), indicating significant neural damage by VNS. Conclusion The optimal titration of VNS would maximize benefits for CHF and minimize adverse effects..
25. Ryo Miyake, Takeo Fujino, Kotaro Abe, Kazuya Hosokawa, Kisho Ohtani, Hiroko Morisaki, Osamu Yamada, Taiki Higo, Tomomi Ide, Pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia successfully treated with sildenafil, International Journal of Cardiology, 10.1016/j.ijcard.2016.03.211, 214, 275-276, 2016.07.
26. Masataka Ikeda, Yasuhiro Sezutsu, takafumi sakamoto, Tomomi Ide, Electron microscopy reveals morphosis of multi-layered mitochondria in the myocardium of a patient with mitochondrial cardiomyopathy, European heart journal, 10.1093/eurheartj/ehv764, 37, 17, 2016.05.
27. Keita Saku, Takamori Kakino, Takahiro Arimura, takafumi sakamoto, Takuya Nishikawa, Kazuo Sakamoto, Masataka Ikeda, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Total mechanical unloading minimizes metabolic demand of left ventricle and dramatically reduces infarct size in myocardial infarction, PloS one, 10.1371/journal.pone.0152911, 11, 4, 2016.04, Background: Left ventricular assist device (LVAD) mechanically unloads the left ventricle (LV). Theoretical analysis indicates that partial LVAD support (p-LVAD), where LV remains ejecting, reduces LV preload while increases afterload resulting from the elevation of total cardiac output and mean aortic pressure, and consequently does not markedly decrease myocardial oxygen consumption (MVO2). In contrast, total LVAD support (t-LVAD), where LV no longer ejects, markedly decreases LV preload volume and afterload pressure, thereby strikingly reduces MVO2. Since an imbalance in oxygen supply and demand is the fundamental pathophysiology of myocardial infarction (MI), we hypothesized that t-LVAD minimizes MVO2 and reduces infarct size in MI. The purpose of this study was to evaluate the differential impact of the support level of LVAD on MVO2 and infarct size in a canine model of ischemia-reperfusion. Methods: In 5 normal mongrel dogs, we examined the impact of LVAD on MVO2 at 3 support levels: Control (no LVAD support), p-LVAD and t-LVAD. In another 16 dogs, ischemia was induced by occluding major branches of the left anterior descending coronary artery (90 min) followed by reperfusion (300 min). We activated LVAD from the beginning of ischemia until 300 min of reperfusion, and compared the infarct size among 3 different levels of LVAD support. Results: t-LVAD markedly reduced MVO2 (% reduction against Control: -56 ± 9%, p<0.01) whereas p-LVAD did less (-21 ± 14%, p<0.05). t-LVAD markedly reduced infarct size compared to p-LVAD (infarct area/area at risk: Control; 41.8 ± 6.4, p-LVAD; 29.1 ± 5.6 and t-LVAD; 5.0 ± 3.1%, p<0.01). Changes in creatine kinase-MB paralleled those in infarct size. Conclusions: Total LVAD support that minimizes metabolic demand maximizes the benefit of LVAD in the treatment of acute myocardial infarction..
28. Tomoki Ushijima, Yoshihisa Tanoue, Tomomi Ide, Shinji Okano, Yoshinao Oda, Ryuji Tominaga, Disuse Atrophy of the Aortic Valve After Left Ventricular Assist Device Implantation, Annals of Thoracic Surgery, 10.1016/j.athoracsur.2015.03.047, 101, 2, 742-744, 2016.02, A 31-year-old woman underwent implantation of a DuraHeart left ventricular assist device as bridge to transplantation. Aortic insufficiency was not observed before implantation but developed after implantation and became severe approximately 2 years later. Macroscopically, the aortic valve excised during heart transplantation showed no morphologic alteration. Microscopically, the collagen fibers in the fibrosa layer and the elastic fibers in the ventricularis layer of the valve leaflets were reduced in number, with irregular arrangement. These characteristics can be explained by a disuse atrophic change, and may lead to a better understanding of the mechanism underlying the development of aortic insufficiency..
29. Kazuo Sakamoto, Kazuya Hosokawa, Keita Saku, takafumi sakamoto, Tomoyuki Tobushi, Yasuhiro Oga, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Baroreflex failure increases the risk of pulmonary edema in conscious rats with normal left ventricular function, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00610.2015, 310, 2, H199-H205, 2016.01, In heart failure with preserved ejection fraction (HFpEF), the complex pathogenesis hinders development of effective therapies. Since HFpEF and arteriosclerosis share common risk factors, it is conceivable that stiffened arterial wall in HFpEF impairs baroreflex function. Previous investigations have indicated that the baroreflex regulates intravascular stressed volume and arterial resistance in addition to cardiac contractility and heart rate. We hypothesized that baroreflex dysfunction impairs regulation of left atrial pressure (LAP) and increases the risk of pulmonary edema in freely moving rats. In 15-wk Sprague-Dawley male rats, we conducted sinoaortic denervation (SAD, n = 6) or sham surgery (Sham, n = 9), and telemetrically monitored ambulatory arterial pressure (AP) and LAP. We compared the mean and SD (lability) of AP and LAP between SAD and Sham under normal-salt diet (NS) or high-salt diet (HS). SAD did not increase mean AP but significantly increased AP lability under both NS (P = 0.001) and HS (P = 0.001). SAD did not change mean LAP but significantly increased LAP lability under both NS (SAD: 2.57 ± 0.43 vs. Sham: 1.73 ± 0.30 mmHg, P = 0.01) and HS (4.13 ± 1.18 vs. 2.45 ± 0.33 mmHg, P = 0.02). SAD markedly increased the frequency of high LAP, and SAD with HS prolonged the duration of LAP > 18 mmHg by nearly 20-fold compared with Sham (SAD ± HS: 2,831 ± 2,366 vs. Sham ± HS: 148 ± 248 s, P = 0.01). We conclude that baroreflex failure impairs volume tolerance and together with salt loading increases the risk of pulmonary edema even in the absence of left ventricular dysfunction. Baroreflex failure may contribute in part to the pathogenesis of HFpEF..
30. Takeo Fujino, Taiki Higo, Yoshihisa Tanoue, Tomomi Ide, FDG-PET/CT for driveline infection in a patient with implantable left ventricular assist device, European Heart Journal Cardiovascular Imaging, 10.1093/ehjci/jev234, 17, 1, 2016.01.
31. Akiyuki Nishimura, Caroline Sunggip, Hidetoshi Saitoh, Tsukasa Shimauchi, Takuro Numaga-Tomita, Katsuya Hirano, Tomomi Ide, Jean Marie Boeynaems, Hitoshi Kurose, Tsuda Makoto, Bernard Robaye, Kazuhide Inoue, Motohiro Nishida, Purinergic P2Y6 receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension, Science Signaling, 10.1126/scisignal.aac9187, 9, 411, 2016.01, The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR), promoted Ang II-induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II-induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein-dependent vascular hypertrophy but reduced b-arrestin-dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II-induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascularsmoothmuscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin-dependent proliferation to G protein- dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II..
32. Shu Ling Liu, Tsubasa Oyama, Yurika Miyoshi, Shiow Yunn Sheu, Masashi Mita, Tomomi Ide, Wolfgang Lindner, Kenji Hamase, Jen Ai Lee, Establishment of a two-dimensional chiral HPLC system for the simultaneous detection of lactate and 3-hydroxybutyrate enantiomers in human clinical samples, Journal of Pharmaceutical and Biomedical Analysis, 10.1016/j.jpba.2015.05.036, 116, 80-85, 2015.12, A two-dimensional chiral high-performance liquid chromatography system was established for simultaneous detection of lactate (LA) and 3-hydroxybutyrate (3HB) enantiomers in human clinical samples. d-LA is increased upon kidney damage but 3HB protected against kidney injury. Therefore, determining the concentrations of d,. l-LA and d,. l-3HB simultaneously would be useful for evaluating pathological conditions. LA and 3HB were pre-column-derivatized with the fluorescent reagent 4-(. N-chloroformylmethyl-. N-methylamino)-7-nitro-2,1,3-benzoxadiazole (NBD-COCl) at 60. °C for 15. min and separated in the first dimension with a capillary monolithic octadecylsilane column. The mobile phase consisted of 13% acetonitrile and 0.05% tirfluoroacetic acid in water. Chiralpak QD-AX and KSAACSP-001S enantioselective columns were used in the second dimension to separate LA and 3HB enantiomers, respectively. Mobile phases were mixed solutions of methanol and acetonitrile containing formic acid. The separation factors were 1.14 and 1.08, respectively. The detection limit of LA and 3HB enantiomers was 10. fmol/injection. This method was applied to human clinical samples; intra- and inter-day relative standard deviations of LA and 3HB enantiomers were, respectively, 1.04-3.25% and 1.61-5.12% in plasma, 9.19-11.2% and 4.60-5.89% in urine, and 7.12-8.90% and 2.86-6.97% in saliva. This novel analytical method is a powerful tool for investigating variations in LA and 3HB enantiomers under disease conditions..
33. Masataka Ikeda, Ide Tomomi, Takeo Fujino, Yuka Matsuo, Shinobu Arai, Keita Saku, Takamori Kakino, Yasuhiro Oga, Akiko Nishizaki, Kenji Sunagawa, The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload, SCIENTIFIC REPORTS, 10.1038/srep15881, 5, 2015.10.
34. Krish Chandrasekaran, Muragundla Anjaneyulu, Tatsuya Inoue, Joungil Choi, Avinash Rao Sagi, Chen Chen, Ide Tomomi, James W. Russell, Mitochondrial transcription factor A regulation of mitochondrial degeneration in experimental diabetic neuropathy, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 10.1152/ajpendo.00620.2014, 309, 2, E132-E141, 2015.07.
35. Tomomi Ide, Role of mitochondria and reactive oxygen species in heart failure, Japanese Journal of Clinical Chemistry, 44, 3, 191-197, 2015.07.
36. Masataka Ikeda, Ide Tomomi, Shinobu Arai, Keita Saku, Takamori Kakino, Henna Tyynismaa, Toshihide Yamasaki, Ken-ichi Yamada, Dongchon Kang, Anu Suomalainen, Kenji Sunagawa, Overexpression of TFAM or Twinkle Increases mtDNA Copy Number and Facilitates Cardioprotection Associated with Limited Mitochondrial Oxidative Stress, PLOS ONE, 10.1371/journal.pone.0119687, 10, 3, 2015.03.
37. takafumi sakamoto, Takamori Kakino, Kazuo Sakamoto, Tomoyuki Tobushi, Atsushi Tanaka, Keita Saku, Kazuya Hosokawa, Ken Onitsuka, Yoshinori Murayama, Takaki Tsutsumi, Tomomi Ide, Kenji Sunagawa, Changes in vascular properties, not ventricular properties, predominantly contribute to baroreflex regulation of arterial pressure, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00552.2014, 308, 1, H49-H58, 2015.01, Baroreflex modulates both the ventricular and vascular properties and stabilizes arterial pressure (AP). However, how changes in those mechanical properties quantitatively impact the dynamic AP regulation remains unknown. We developed a framework of circulatory equilibrium, in which both venous return and cardiac output are expressed as functions of left ventricular (LV) end-systolic elastance (Ees), heart rate (HR), systemic vascular resistance (R), and stressed blood volume (V). We investigated the contribution of each mechanical property using the framework of circulatory equilibrium. In six anesthetized dogs, we vascularly isolated carotid sinuses and randomly changed carotid sinus pressure (CSP), while measuring the LV Ees, aortic flow, right and left atrial pressure, and AP for at least 60 min. We estimated transfer functions from CSP to Ees, HR, R, and V in each dog. We then predicted these parameters in response to changes in CSP from the transfer functions using a data set not used for identifying transfer functions and predicted changes in AP using the equilibrium framework. Predicted APs matched reasonably well with those measured (r2= 0.85–0.96, P < 0.001). Sensitivity analyses indicated that Ees and HR (ventricular properties) accounted for 14 ± 4 and 4 ± 2%, respectively, whereas R and V (vascular properties) accounted for 32 ± 4 and 39 ± 4%, respectively, of baroreflex-induced AP regulation. We concluded that baroreflex-induced dynamic AP changes can be accurately predicted by the transfer functions from CSP to mechanical properties using our framework of circulatory equilibrium. Changes in the vascular properties, not the ventricular properties, predominantly determine baroreflex-induced AP regulation..
38. Kazuo Sakamoto, Keita Saku, Takuya Kishi, Takamori Kakino, Atsushi Tanaka, takafumi sakamoto, Tomomi Ide, Kenji Sunagawa, Prediction of the impact of venoarterial extracorporeal membrane oxygenation on hemodynamics, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00603.2014, 308, 8, H921-H930, 2015.01, Although venoarterial extracorporeal membrane oxygenation (ECMO) was developed to rescue patients with cardiogenic shock, the impact of ECMO on hemodynamics is often unpredictable and can lead to hemodynamic collapse. In this study, we developed a framework in which we incorporated ECMO into the extended Guyton's model of circulatory equilibrium and predicted hemodynamic changes in response to ECMO. We first determined the cardiac output (CO) curves of left and right heart (to generate the integrated CO curve) without ECMO in eight normal and seven dogs with left ventricular dysfunction. Using the CO curves obtained and standard parameters for the venous return surface, we predicted the circulatory equilibrium under various levels of ECMO support. The predicted total flow (native left heart flow plus ECMO flow), right atrial pressure (PRA), and left atrial pressure (PLA) matched well with those measured [total flow: coefficient of determination (r2) = 0.99, standard error of estimate (SEE) = 5.8 ml•min−1•kg−1, PRA: r2 = 0.95, SEE = 0.23 mmHg, PLA: r2 = 0.99, SEE = 0.59 mmHg]. Lastly, we estimated the CO curves under ECMO support from minute changes in hemodynamics induced by change in ECMO. From the CO curves estimated, we predicted the circulatory equilibrium. The predicted total flow (r2 = 0.93, SEE = 0.5 ml•min−1•kg−1), PRA (r2 = 0.99, SEE = 0.54 mmHg), and PLA (r2 = 0.95, SEE = 0.89 mmHg) matched reasonably well with those measured. A numerical simulation indicated that ECMO support may cause pulmonary edema, if right ventricular function is compromised. We conclude that the proposed framework may enhance the benefit and reduce the risk of ECMO support in patients with critical hemodynamic conditions..
39. Keita Saku, Takuya Kishi, Kazuo Sakamoto, Kazuya Hosokawa, Takafumi Sakamoto, Yoshinori Murayama, Takamori Kakino, Masataka Ikeda, Ide Tomomi, Kenji Sunagawa, Afferent vagal nerve stimulation resets baroreflex neural arc and inhibits sympathetic nerve activity, Vol.2, Iss 9 e12136, 2014.09.
40. Keita Saku, Akiko Nishizaki, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Stimulus frequency differences in respiratory inhibition is negligible to optimize vagal nerve stimulation (VNS) for heart failure, BME = Bio medical engineering / henshu, Nihon ME Gakkai, 10.11239/jsmbe.52.O-84, 52, O-84-O-85, 2014.08, Although VNS benefits for heart failure, up titrations are limited in 72 % of human subject because of respiratory side effects. Since vagal nerves are connected to the respiratory center in brainstem, VNS is possible to change respiratory rhythms. In this study, we investigated how the frequency differences in VNS impact on respiration. In Sprague-Dawley rats (N=4), we changed the stimulus frequencies (5, 10, 20, and 50 Hz) and amplitude of VNS (0-8 V). In low frequencies (5 and 10 Hz), VNS slightly inhibited respiration with stimulus amplitudes. Maximum inhibition of minute ventilation was -18.4 ± 0.1 % in 5 Hz and -47.1 ± 2.7 % in 10 Hz. While in high frequencies (20 and 50 Hz), VNS induced apnea above 2-4 V. In conclusion, high stimulus frequency induced remarkable respiratory inhibition and apnea. It is negligible effect to titrate VNS..
41. 船越 公太, 細川 和也, 岸 拓弥, 井手 友美, 砂川 賢二, Striking Volume Intolerance Is Induced by Mimicking Arterial Baroreflex Failure in Normal Left Ventricular Function, JOURNAL OF CARDIAC FAILURE, 10.1016/j.cardfail.2013.11.007, 20, 1, 53-59, 2014.01.
42. Keita Saku, Takuya Kishi, Kazuo Sakamoto, Kazuya Hosokawa, takafumi sakamoto, Yoshinori Murayama, Takamori Kakino, Masataka Ikeda, Tomomi Ide, Kenji Sunagawa, Afferent vagal nerve stimulation resets baroreflex neural arc and inhibits sympathetic nerve activity, Physiological Reports, 10.14814/phy2.12136, 2, 9, 2014.01, It has been established that vagal nerve stimulation (VNS) benefits patients and/or animals with heart failure. However, the impact of VNS on sympathetic nerve activity (SNA) remains unknown. In this study, we investigated how vagal afferent stimulation (AVNS) impacts baroreflex control of SNA. In 12 anesthetized Sprague–Dawley rats, we controlled the pressure in isolated bilateral carotid sinuses (CSP), and measured splanchnic SNA and arterial pressure (AP). Under a constant CSP, increasing the voltage of AVNS dose dependently decreased SNA and AP. The averaged maximal inhibition of SNA was -28.0 ± 10.3%. To evaluate the dynamic impacts of AVNS on SNA, we performed random AVNS using binary white noise sequences, and identified the transfer function from AVNS to SNA and that from SNA to AP. We also identified transfer functions of the native baroreflex from CSP to SNA (neural arc) and from SNA to AP (peripheral arc). The transfer function from AVNS to SNA strikingly resembled the baroreflex neural arc and the transfer functions of SNA to AP were indistinguishable whether we perturbed ANVS or CSP, indicating that they likely share common central and peripheral neural mechanisms. To examine the impact of AVNS on baroreflex, we changed CSP stepwise and measured SNA and AP responses with or without AVNS. AVNS resets the sigmoidal neural arc downward, but did not affect the linear peripheral arc. In conclusion, AVNS resets the baroreflex neural arc and induces sympathoinhibition in the same manner as the control of SNA and AP by the native baroreflex..
43. Takahiro Arimura, Keita Saku, Takamori Kakino, Takuya Akashi, Takako Takehara, Akiko Nishizaki, Yasuhiro Oga, Masataka Ikeda, Kana Fujii, Tomomi Ide, Takuya Kishi, Kenji Sunagawa, Total left ventricular unloading markedly reduces the pressure-volume area, thereby oxygen consumption, BME = Bio medical engineering / henshu, Nihon ME Gakkai, 10.11239/jsmbe.52.O-548, 52, O-548-O-549, 2014.01, Left ventricular assist device (LVAD) unloads LV and exerts better outcome in both acute coronary syndrome and severe heart failure. In this study, we investigate how the degree of LVAD support impacts on the hemodynamics and oxygen consumption of left ventricle. Methods/Results: We used 5 dogs and changed LVAD support at 3 levels, no support, Partial (LV remains ejecting) and Total (total LVAD dependent circulation). Mean aortic pressure were not different among 3 groups, while peak systolic pressure of LV reduced in Total (108±8.6 vs 102±3.3 vs 42±11mmHg, p<0.05). The pressure-volume area (PVA) indicating oxygen consumption of LV significantly reduced in Partial, while markedly reduced in Total (2040±632 vs 1787±547 vs 487±160 ml·mmHg, p<0.05). Conclusions: Total unloading minimizes oxygen consumption of left ventricle. Appropriate unloading minimizes oxygen consumption and enables us to maximize the beneficial effect of LVAD in heart disease..
44. Kana Fujii, Takahiro Arimura, Keita Saku, Takamori Kakino, Takuya Akashi, Tomomi Ide, Takuya Kishi, Kenji Sunagawa, Transvenous vagal nerve stimulation (VNS) in acute myocardial infarction (AMI) reduces the infarct size and improves long term cardiac function, BME = Bio medical engineering / henshu, Nihon ME Gakkai, 10.11239/jsmbe.52.O-86, 52, O-86-O-87, 2014.01, VNS is known to have an anti-infarct effect. However, the technical difficulty associated with VNS precludes its application under clinical settings of AMI. We developed a novel technique where we stimulate the vagal nerves transvenously, and evaluated how the VNS affects the infarction size and cardiac function in the long term. We ligated the left anterior descending coronary artery for 3 hours, then reperfused. For transvenous VNS, we performed the field electrical stimulation at the superior vena cava. One month after the ischemia-reperfusion, we compared the infarct size and cardiac function with/without VNS. Transvenous VNS significantly decreased the infarction size by more than 80% (1.1±1.2 vs. 7.8±1.2cm2, p<0.05), doubled left ventricular systolic elastance (13.2±0.6 vs. 6.5±1.7 mmHg/ml, p<0.05), and decreased NT-pro BNP (843±256 vs. 3667±1637 pmol/ml, p<0.05). In conclusion, transvenous VNS in AMI markedly reduces the infarct size and improves cardiac function in the long term..
45. Toshiro Saito, mayumi hirano, Ide Tomomi, Katsuya Hirano, Pivotal Role of Rho-Associated Kinase 2 in Generating the Intrinsic Circadian Rhythm of Vascular Contractility, CIRCULATION, 10.1161/CIRCULATIONAHA.112.135608, 127, 1, 104-+, 2013.01.
46. Nakaya Michio, Satsuki Chikura, Kenji Watari, Natsumi Mizuno, Koji Mochinaga, Supachoke Mangmool, Koyanagi Satoru, Shigehiro Ohdo, Yoji Sato, Tomomi Ide, Motohiro Nishida, Hitoshi Kurose, Induction of cardiac fibrosis by β-blocker in G protein-independent and G protein-coupled receptor kinase 5/β-arrestin2-dependent signaling pathways, Journal of Biological Chemistry, 10.1074/jbc.M112.357871, 287, 42, 35669-35677, 2012.10, G-protein coupled receptors (GPCRs) have long been known as receptors that activate G protein-dependent cellular signaling pathways. In addition to the G protein-dependent pathways, recent reports have revealed that several ligands called "biased ligands" elicit G protein-independent and β-arrestin-dependent signaling through GPCRs (biased agonism). Several β-blockers are known as biased ligands. All β-blockers inhibit the binding of agonists to the β-adrenergic receptors. In addition to β-blocking action, some β-blockers are reported to induce cellular responses through G protein-independent and β-arrestin-dependent signaling pathways. However, the physiological significance induced by the β-arrestin-dependent pathway remains much to be clarified in vivo. Here, we demonstrate that metoprolol, a β1-adrenergic receptor-selective blocker, could induce cardiac fibrosis through a G protein-independent and β-arrestin2-dependent pathway. Metoprolol, a β-blocker, increased the expression of fibrotic genes responsible for cardiac fibrosis in cardiomyocytes. Furthermore, metoprolol induced the interaction between β1- adrenergic receptor and β-arrestin2, but not β-arrestin1. The interaction between β1-adrenergic receptor and β-arrestin2 by metoprolol was impaired in the G protein-coupled receptor kinase 5 (GRK5)- knockdown cells. Metoprolol-induced cardiac fibrosis led to cardiac dysfunction. However, the metoprolol-induced fibrosis and cardiac dysfunction were not evoked in β-arrestin2- or GRK5-knock-out mice. Thus, metoprolol is a biased ligand that selectively activates a G protein-independent and GRK5/β-arrestin2-dependent pathway, and induces cardiac fibrosis. This study demonstrates the physiological importance of biased agonism, and suggests that G protein-independent and β-arrestindependent signaling is a reason for the diversity of the effectiveness of β-blockers..
47. 細川和也, 井手 友美, 戸伏倫之, 坂本和生, 鬼塚 健, 坂本隆文, 藤野剛雄, 朔啓太, 砂川賢二, Bionic Baroreceptor Corrects Postural Hypotension in Rats With Impaired Baroreceptor, CIRCULATION, 10.1161/CIRCULATIONAHA.112.108357, 126, 10, 1278-1285, 2012.09.
48. 藤野 剛雄, 井手 友美, 吉田 昌義, 鬼塚 健, 田中 敬士, 秦 優子, 西田 基宏, Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes, MITOCHONDRION, 10.1016/j.mito.2012.06.002, 12, 4, 449-458, 2012.07.
49. Morimoto N, Miyazaki K, Kurata T, Ikeda Y, Matsuura T, Kang D, Ide T, Abe K., Effect of mitochondrial transcription factor a overexpression on motor neurons in amyotrophic lateral sclerosis model mice., 90, 6, 1200-1208, 2012.06.
50. Nobutoshi Morimoto, Kazunori Miyazaki, Tomoko Kurata, Yoshio Ikeda, Tohru Matsuura, Dongchon Kang, Tomomi Ide, Koji Abe, Effect of mitochondrial transcription factor a overexpression on motor neurons in amyotrophic lateral sclerosis model mice, Journal of Neuroscience Research, 10.1002/jnr.23000, 90, 6, 1200-1208, 2012.06, Increasing evidence indicates that oxidative stress is an important mechanism underlying motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS). Mitochondrial DNA (mtDNA) is highly susceptible to oxidative damage and has little potential for repair, although mitochondrial transcription factor A (TFAM) plays essential roles in maintaining mitochondrial DNA by reducing oxidative stress, promoting mtDNA transcription, and regulating mtDNA copy number. To analyze a possible therapeutic effect of TFAM on ALS pathology, double transgenic mice overexpressing G93A mutant SOD1 (G93ASOD1) and human TFAM (hTFAM) were newly generated in the present study. Rotarod scores were better in G93ASOD1/hTFAM double-Tg mice than G93ASOD1 single-Tg mice at an early symptomatic stage, 15 and 16 weeks of age, with a 10% extension of the onset age in double-Tg mice. The number of surviving MNs was 30% greater in double-Tg mice with end-stage disease, at 19 weeks, with remarkable reductions in the amount of the oxidative stress marker 8-OHdG and the apoptotic marker cleaved caspase 3 and with preserved COX1 expression. Double-immunofluorescence study showed that hTFAM was expressed specifically in MNs and microglia in the spinal cords of double-Tg mice. The present study suggests that overexpression of TFAM has a potential to reduce oxidative stress in MN and delay onset of the disease in ALS model mice..
51. Masao Takemoto, Yasushi Mukai, Shuujirou Inoue, Tetsuya Matoba, Mari Nishizaka, Tomomi Ide, Akiko Chishaki, Kenji Sunagawa, Usefulness of non-contact mapping for radiofrequency catheter ablation of inappropriate sinus tachycardia
New procedural strategy and long-term clinical outcome, Internal Medicine, 10.2169/internalmedicine.51.5882, 51, 4, 357-362, 2012.02, Objectives The present study evaluated the clinical benefits of a new therapeutic method of radiofrequency catheter ablation (RFCA) using an EnSite system for inappropriate sinus tachycardia (IST). Materials and Methods Six patients with debilitating IST underwent RFCA using EnSite. Using the betaadrenergic blocker and agonist, the heart rate was controlled between 70 to 150 bpm before and after the RFCA. The areas of the breakout sites (BOSs) were clearly distinguished between those from the normal Pwave zones during rates of less than 100 bpm and those from more upper rate sites during rates of more than 100 bpm using the EnSite system, in accordance with the appearance of tall P-waves (tall P-wave zone) in the IST patients. This was selected as the target for ablation. Results After the RFCA, the BOSs observed during heart rates of more than 100 bpm moved completely from the tall P-wave zone to the normal P-wave zone in the IST patients. The total number of heart beats and average heart beat on the 24-h Holter monitoring decreased statistically from that before the RFCA to that after, and no adverse heart rate responses was observed after the RFCA. Before the RFCA, the brain natriuretic peptide was elevated, New York Heart Association functional class was worse, and there was an impaired exercise tolerance observed with exercise electrocardiogram testing. The RFCA for the IST significantly improved those parameters. Conclusion This new therapeutic method for IST using EnSite is effective and produces clinical benefits..
52. Mayumi Yamato, Takeshi Shiba, Tomomi Ide, Naoko Seri, Wataru Kudo, Makoto Ando, Ken-Ichi Yamada, Shintaro Kinugawa, Hiroyuki Tsutsui, High-fat diet-induced obesity and insulin resistance were ameliorated via enhanced fecal bile acid excretion in tumor necrosis factor-alpha receptor knockout mice, Molecular and cellular biochemistry, 10.1007/s11010-011-1010-3, 359, 1-2, 161-167, 2012.01, Tumor necrosis factor-α (TNF-α) is one of the main mediators of inflammatory response activated by fatty acids in obesity, and this signaling through TNF-α receptor (TNFR) is responsible for obesity-associated insulin resistance. Recently, TNF-α has shown to affect lipid metabolism including the regulation of lipase activity and bile acid synthesis. However, there is scanty in vivo evidence for the involvement of TNF-α in this process, and the mechanistic role of TNFR remains unclear. In this study, TNFR2 knockout mice (R2KO) and wild-type (WT) mice were fed commercial normal diet (ND) or high-fat diet (HFD) for 8 weeks. In R2KO/HFD mice, the increase in body weight and the accumulation of fat were significantly ameliorated compared with WT/HFD mice in association with the decrease in plasma total cholesterol (137.7 ± 3.1 vs. 98.6 ± 3.1 mg/dL, P < 0.005), glucose (221.9 ± 14.7 vs. 167.3 ± 8.1 mg/dL, P < 0.01), and insulin (5.1 ± 0.3 vs. 3.4 ± 0.3 ng/mL, P < 0.05). Fecal excretion of lipid contents was significantly increased in R2KO mice. In R2KO/HFD mice, the decrease in hepatic cholesterol-7a-hydroxylase activity, the rate-limiting enzyme in bile acid synthesis, was inhibited (1.7 ± 0.2 vs. 8.1 ± 1.0 pmol/min/mg protein, P < 0.01). These results suggested that HFD-induced obesity with metabolic derangements could be ameliorated in mice lacking TNF-α receptor 2 via increasing fecal bile acid and lipid content excretion. Therefore, TNF-α signaling through TNFR2 is essentially involved in the bile acid synthesis and excretion of lipids, resulting in its beneficial effects..
53. Tomomi Ide, Kenji Sunagawa, [Chronic heart failure
progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment; 1. Prevention for chronic heart failure]., Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 101, 2, 369-374, 2012.01.
54. Kazuya Hosokawa, Kouta Funakoshi, Atsushi Tanaka, takafumi sakamoto, Ken Onitsuka, Kazuo Sakamoto, Tomoyuki Tobushi, Takeo Fujino, Keita Saku, Yoshinori Murayama, Tomomi Ide, Kenji Sunagawa, Artificial baroreflex system restores volume tolerance in the absence of native baroreflex, 33rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS 2011 33rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS 2011, 10.1109/IEMBS.2011.6090157, 697-699, 2011.12, The arterial baroreflex stabilizes arterial pressure by modulating the mechanical properties of cardiovascular system. We previously demonstrated that the baroreflex impairment makes the circulatory system extremely sensitive to volume overload and predisposes to pulmonary edema irrespective of left ventricular systolic function. To overcome the volume intolerance, we developed an artificial baroreflex system by directly stimulating the carotid sinus nerves in response to changes in arterial pressure. The artificial baroreflex system precisely reproduced the native arterial pressure response and restored physiological volume buffering function. We conclude that the artificial baroreflex system would be an attractive tool in preventing pulmonary edema in patients with impaired baroreflex function..
55. Kazuya Hosokawa, Kouta Funakoshi, Atsushi Tanaka, takafumi sakamoto, Ken Onitsuka, Kazuo Sakamoto, Tomoyuki Tobushi, Takeo Fujino, Keita Saku, Yoshinori Murayama, Tomomi Ide, Kenji Sunagawa, Artificial baroreflex system restores volume tolerance in the absence of native baroreflex, 33rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS 2011 33rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS 2011, 10.1109/IEMBS.2011.6090157, 697-699, 2011.12, The arterial baroreflex stabilizes arterial pressure by modulating the mechanical properties of cardiovascular system. We previously demonstrated that the baroreflex impairment makes the circulatory system extremely sensitive to volume overload and predisposes to pulmonary edema irrespective of left ventricular systolic function. To overcome the volume intolerance, we developed an artificial baroreflex system by directly stimulating the carotid sinus nerves in response to changes in arterial pressure. The artificial baroreflex system precisely reproduced the native arterial pressure response and restored physiological volume buffering function. We conclude that the artificial baroreflex system would be an attractive tool in preventing pulmonary edema in patients with impaired baroreflex function..
56. Yamato M, Shiba T, Ide T, Honda Y, Yamada K, Tsutsui H., Nifedipine treatment reduces brain damage after transient focal ischemia, possibly through its antioxidative effects., Hypertension Research, 34, 7, 840-845, 2011.07.
57. Mayumi Yamato, Takeshi Shiba, Tomomi Ide, Youhei Honda, Ken-Ichi Yamada, Hiroyuki Tsutsui, Nifedipine treatment reduces brain damage after transient focal ischemia, possibly through its antioxidative effects, Hypertension Research, 10.1038/hr.2011.51, 34, 7, 840-845, 2011.07, Stroke is a major cause of mortality and morbidity in hypertensive patients. This study investigated the effects of nifedipine, an L-type voltage-gated Ca 2+ channel blocker, on ischemic lesion volume after focal cerebral ischemia and reperfusion in rats. Rats were subjected to 1 h of transient middle cerebral artery occlusion (MCAO). At 2 days after MCAO, the rats were randomized into two groups that were fed either a normal control diet (n=10) or a nifedipine (0.001%) containing diet (n=11) for 2 weeks. Nifedipine treatment significantly reduced ischemic lesion volume (116.5±10.8 vs. 80.0±8.2 mm 3, P<0.05) without affecting body weight or blood pressure. It also decreased thiobarbituric-reactive substances, an index of lipid peroxide, (2.6±0.4 vs. 1.7±0.1 mol g -1 tissue, P<0.05) and increased glutathione peroxidase (54.9±4.7 vs. 70.9±6.4 U g -1 protein, P<0.05) and glutathione reductase activities (32.4±1.4 vs. 39.9±2.7 U g -1 protein, P<0.05) in the mitochondria from the ischemic hemispheres. These results suggest that nifedipine treatment can reduce ischemic lesion volume after focal cerebral ischemia, possibly because of the decrease in oxidative stress with an increase in antioxidant activities within the ischemic area..
58. Yikallio E. Ylikallio E, Page JL, Xu X, Lampinen M, Bepler G, Ide T, Tyynismaa H, Weiss RS, Suomalainen A, Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice., Nucleic Acids Res, 38, 8208-8218, 2011.05.
59. Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H, Nishida M., TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts., Biochem Biophys Res Commun, 409, 1, 108-113, 2011.05.
60. Naoyuki Kitajima, Kunihiro Watanabe, Sachio Morimoto, Yoji Sato, Shigeki Kiyonaka, Masahiko Hoshijima, Yasuhiro Ikeda, Nakaya Michio, Tomomi Ide, Yasuo Mori, Hitoshi Kurose, Motohiro Nishida, TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2011.04.124, 409, 1, 108-113, 2011.05, Dilated cardiomyopathy (DCM) is a myocardial disorder that is characterized by dilation and dysfunction of the left ventricle (LV). Accumulating evidence has implicated aberrant Ca2+ signaling and oxidative stress in the progression of DCM, but the molecular details are unknown. In the present study, we report that inhibition of the transient receptor potential canonical 3 (TRPC3) channels partially prevents LV dilation and dysfunction in muscle LIM protein-deficient (MLP (-/-)) mice, a murine model of DCM. The expression level of TRPC3 and the activity of Ca2+/calmodulin-dependent kinase II (CaMKII) were increased in MLP (-/-) mouse hearts. Acitivity of Rac1, a small GTP-binding protein that participates in NADPH oxidase (Nox) activation, and the production of reactive oxygen species (ROS) were also increased in MLP (-/-) mouse hearts. Treatment with pyrazole-3, a TRPC3 selective inhibitor, strongly suppressed the increased activities of CaMKII and Rac1, as well as ROS production. In contrast, activation of TRPC3 by 1-oleoyl-2-acetyl-sn-glycerol (OAG), or by mechanical stretch, induced ROS production in rat neonatal cardiomyocytes. These results suggest that up-regulation of TRPC3 is responsible for the increase in CaMKII activity and the Nox-mediated ROS production in MLP (-/-) mouse cardiomyocytes, and that inhibition of TRPC3 is an effective therapeutic strategy to prevent the progression of DCM..
61. Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim KM, Ide T, Sato Y, Inoue K, Kurose H., Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-kappaB., Proc Natl Acad Sci U S A., 108, 16, 6662-6667, 2011.04.
62. Motohiro Nishida, Mariko Ogushi, Reiko Suda, Miyuki Toyotaka, Shota Saiki, Naoyuki Kitajima, Nakaya Michio, Kyeong Man Kim, Tomomi Ide, Yoji Sato, Kazuhide Inoue, Hitoshi Kurose, Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-κB, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1017640108, 108, 16, 6662-6667, 2011.04, Cross-talk between G protein-coupled receptor (GPCR) signaling pathways serves to fine tune cellular responsiveness by neurohumoral factors. Accumulating evidence has implicated nitric oxide (NO)-based signaling downstream of GPCRs, but the molecular details are unknown. Here, we show that adenosine triphosphate (ATP) decreases angiotensin type 1 receptor (AT 1R) density through NO-mediated S-nitrosylation of nuclear factor κB (NF-κB) in rat cardiac .broblasts. Stimulation of purinergic P2Y2 receptor by ATP increased expression of inducible NO synthase (iNOS) through activation of nuclear factor of activated T cells, NFATc1 and NFATc3. The ATP-induced iNOS interacted with p65 subunit of NF-κB in the cytosol through .avin-binding domain, which was indispensable for the locally generated NO-mediated S-nitrosylation of p65 at Cys38. β-Arrestins anchored the formation of p65/ IκBα/β-arrestins/iNOS quaternary complex. The S-nitrosylated p65 resulted in decreases in NF-κB transcriptional activity and AT1R density. In pressure-overloaded mouse hearts, ATP released from cardiomyocytes led to decrease in AT 1R density through iNOS-mediated S-nitrosylation of p65. These results show a unique regulatory mechanism of heterologous regulation of GPCRs in which cysteine modi.cation of transcriptional factor rather than protein phosphorylation plays essential roles..
63. Emil Ylikallio, Jennifer L. Page, Xia Xu, Milla Lampinen, Gerold Bepler, Tomomi Ide, Henna Tyynismaa, Robert S. Weiss, Anu Suomalainen, Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice, Nucleic acids research, 10.1093/nar/gkq735, 38, 22, 8208-8218, 2010.12, Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis, with important roles in nuclear genome maintenance. RNR is also essential for maintenance of mitochondrial DNA (mtDNA) in mammals. The mechanisms regulating mtDNA copy number in mammals are only being discovered. In budding yeast, RNR overexpression resulted in increased mtDNA levels, and rescued the disease phenotypes caused by a mutant mtDNA polymerase. This raised the question of whether mtDNA copy number increase by RNR induction could be a strategy for treating diseases with mtDNA mutations. We show here that high-level overexpression of RNR subunits (Rrm1, Rrm2 and p53R2; separately or in different combinations) in mice does not result in mtDNA copy number elevation. Instead, simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis. We also show that endogenous RNR transcripts are downregulated in response to large increases of mtDNA in mice, which is indicative of nuclear-mitochondrial crosstalk with regard to mtDNA copy number. Our results establish that RNR is not limiting for mtDNA copy number in mice, and provide new evidence for the importance of balanced dNTP pools in mtDNA maintenance in postmitotic tissues..
64. Yuan Yuan Wang, Sachio Morimoto, Cheng Kun Du, Qun Wei Lu, Dong Yun Zhan, Takaki Tsutsumi, Tomomi Ide, Yosikazu Miwa, Fumi Takahashi, Toshiyuki Sasaguri, Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy, Cardiovascular research, 10.1093/cvr/cvq133, 87, 4, 636-646, 2010.09, Aims Thyroid hormone (TH) has prominent effects on the heart, and hyperthyroidism is occasionally found to be a cause of dilated cardiomyopathy (DCM). We aim to explore the potential role of TH in the pathogenesis of DCM. Methods and results The pathophysiological role of TH in the heart was investigated using a knock-in mouse model of inherited DCM with a deletion mutation ΔK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T3) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T3 levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T3 from thyroxin, was up-regulated in the DCM mice hearts. The cAMP levels were increased in DCM mice hearts, suggesting that transcriptional up-regulation of Dio2 gene is mediated through the evolutionarily conserved cAMP-response element site in its promoter. Propylthiouracil (PTU), an anti-thyroid drug, prevented the hypertrophic remodelling of the heart in DCM mice and improved their cardiac function and life expectancy. Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK. Dio2 gene expression was also markedly up-regulated in the mice hearts developing similar eccentric hypertrophy after myocardial infarction. Conclusion Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM..
65. Masaaki Hokari, Satoshi Kuroda, Shintaro Kinugawa, Tomomi Ide, Hiroyuki Tsutsui, Yoshinobu Iwasaki, Overexpression of mitochondrial transcription factor A (TFAM) ameliorates delayed neuronal death due to transient forebrain ischemia in mice, Neuropathology, 10.1111/j.1440-1789.2009.01086.x, 30, 4, 401-407, 2010.08, Mitochondrial transcription factor A (TFAM) is an important regulator to maintain mitochondrial DNA copy number. However, no studies have denoted its roles in cerebral ischemia. Therefore, this study was aimed to assess whether the forced overexpression of TFAM ameliorates delayed neuronal death following transient forebrain ischemia. We have established human TFAM-transgenic (Tg) mice. Wild type (WT) and TFAM-Tg mice were subjected to 20-min bilateral common carotid artery occlusion (BCCAO). Immunostaining against cytochrome c was performed to estimate its release from mitochondria at 24 h after 20-min BCCAO. Histological analysis was performed to evaluate the effect of TFAM overexpression on delayed neuronal death at 72 h after 20-min BCCAO. The number of cytochrome c-positive neurons in the hippocampal CA1 sector was significantly smaller in TFAM-Tg mice than in WT mice (P = 0.005). The percentage of viable neurons in the hippocampal CA1 sector was significantly higher in TFAM-Tg mice than in WT mice (P < 0.001), and the number of TUNEL-positive neurons was significantly smaller in TFAM-Tg mice than in WT mice (P < 0.001). Our data strongly suggest that TFAM overexpression can reduce mitochondrial permeability transition and ameliorate delayed neuronal death in the hippocampus after transient forebrain ischemia..
66. Yikallio E, Tyyismaa H, Tsutsui H, Ide T, Suomalainen A, High mitochondrial DNA copy number has detrimental effects in mice, Hum Mol Genom, 13, 2695-2705, 2010.07.
67. Nishioka T, Onishi K, Shimojo N, Nagano Y, Matsusaka H, Ikeuchi M, Ide T, Tsutsui H, Hiroe M, Yoshida T, Imanaka-Yoshida K , Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice., Am J Physiology-Heart and Circulatory Physiology. 2, 298, H1072-1078, 2010.05.
68. Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima N, Ide T, Inoue R, Kurose H. , Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition., J Biol Choem 285:13244-13253 (2010), Am J Physiology-Heart and Circulatory Physiology. 2, 285, 13244-13253, 2010.05.
69. Emil Ylikallio, Henna Tyynismaa, Hiroyuki Tsutsui, Tomomi Ide, Anu Suomalainen, High mitochondrial DNA copy number has detrimental effects in mice, Human Molecular Genetics, 10.1093/hmg/ddq163, 19, 13, 2695-2705, 2010.04, Mitochondrial DNA (mtDNA) is an essential multicopy genome, compacted into protein-DNA clusters called nucleoids. Maintaining an adequate mtDNA copy number is crucial for cellular viability. Loss of mtDNA results in severe human syndromes, whereas increased mtDNA copy number has been suggested to improve survival from myocardial infarction in mice and to be a promising therapeutic strategy for mitochondrial disease. The mechanisms that regulate mtDNA amount and organization are, however, not fully understood. Of the proteins required for mtDNA existence, only the mitochondrial helicase Twinkle and mitochondrial transcription factor A (TFAM) have been shown to increase mtDNA copy number in vivo, when expressed in physiological levels. Here we studied how Twinkle and TFAM affect mtDNA synthesis and nucleoid structure in mice. Using in vivo BrdU labeling, we show that Twinkle specifically regulates de novo mtDNA synthesis. Remarkably, high mtDNA copy number in mice is accompanied by nucleoid enlargement, which in turn correlates with defective transcription, age-related accumulation of mtDNA deletions and respiratory chain (RC) deficiency. Simultaneous overexpression of Twinkle and TFAM in bitransgenic mice has an additive effect on mtDNA copy number, increasing it up to 6-fold in skeletal muscle. Bitransgenic mice also exhibit further enlargement of nucleoids and aggravation of the RC defect. In conclusion, we show that Twinkle acts as a regulator of mtDNA replication initiation, and provide evidence that high mtDNA copy number and alteration of nucleoid architecture may be detrimental to mitochondrial function..
70. Motohiro Nishida, Kenta Watanabe, Yoji Sato, Nakaya Michio, Naoyuki Kitajima, Tomomi Ide, Ryuji Inoue, Hitoshi Kurose, Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition, Journal of Biological Chemistry, 10.1074/jbc.M109.074104, 285, 17, 13244-13253, 2010.04, Activation of Ca2+ signaling induced by receptor stimulation and mechanical stress plays a critical role in the development of cardiac hypertrophy. A canonical transient receptor potential protein subfamily member, TRPC6, which is activated by diacylglycerol and mechanical stretch, works as an upstream regulator of the Ca2+ signaling pathway. Although activation of protein kinase G (PKG) inhibits TRPC6 channel activity and cardiac hypertrophy, respectively, it is unclear whether PKG suppresses cardiac hypertrophy through inhibition of TRPC6. Here, we show that inhibition of cGMP-selective PDE5 (phosphodiesterase 5) suppresses endothelin-1-, diacylglycerol analog-, and mechanical stretch-induced hypertrophy through inhibition of Ca2+ influx in rat neonatal cardiomyocytes. Inhibition of PDE5 suppressed the increase in frequency of Ca2+ spikes induced by agonists or mechanical stretch. However, PDE5 inhibition did not suppress the hypertrophic responses induced by high KCl or the activation of protein kinase C, suggesting that PDE5 inhibition suppresses Ca2+ influx itself or molecule(s) upstream of Ca2+ influx. PKG activated by PDE5 inhibition phosphorylated TRPC6 proteins at Thr69 and prevented TRPC6-mediated Ca2+ influx. Substitution of Ala for Thr69 in TRPC6 abolished the anti-hypertrophic effects of PDE5 inhibition. In addition, chronic PDE5 inhibition by oral sildenafil treatment actually induced TRPC6 phosphorylation in mouse hearts. Knockdown of RGS2 (regulator of G protein signaling 2) and RGS4, both of which are activated by PKG to reduce Gαq-mediated signaling, did not affect the suppression of receptor-activated Ca2+ influx by PDE5 inhibition. These results suggest that phosphorylation and functional suppression of TRPC6 underlie prevention of pathological hypertrophy by PDE5 inhibition..
71. Tomohiro Nishioka, Katsuya Onishi, Naoshi Shimojo, Yuka Nagano, Hidenori Matsusaka, Masaki Ikeuchi, Tomomi Ide, Hiroyuki Tsutsui, Michiaki Hiroe, Toshimichi Yoshida, Kyoko Imanaka-Yoshida, Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00255.2009, 298, 3, 2010.03, Tenascin-C (TN-C) is an extracellular matrix glycoprotein with high bioactivity. It is expressed at low levels in normal adult heart, but upregulated under pathological conditions, such as myocardial infarction (MI). Recently, we (Ref. 34) reported that MI patients with high serum levels of TN-C have a greater incidence of maladaptive cardiac remodeling and a worse prognosis. We hypothesized that TN-C may aggravate left ventricular remodeling. To examine the effects of TN-C, MI was induced by ligating coronary arteries of TN-C knockout (KO) mice under anesthesia and comparing them with sibling wild-type (WT) mice. In WT+MI mice, TN-C expression was upregulated at day 1, peaked at day 5, downregulated and disappeared by day 28, and the molecule was localized in the border zone between intact myocardium and infarct lesions. The morphometrically determined infarct size and survival rate on day 28 were comparable between the WT+MI and KO+MI groups. Echocardiography and hemodynamic analyses demonstrated left ventricular end-diastolic diameter, myocardial stiffness, and left ventricular end-diastolic pressure to be significantly increased in both WT+MI and KO+MI mice compared with sham-operated mice. However, end-diastolic pressure and dimension and myocardial stiffness of KO+MI were lower than those of the WT+MI mice. Histological examination revealed normal tissue healing, but interstitial fibrosis in the residual myocardium in peri-infarcted areas was significantly less pronounced in KO+MI mice than in WT+MI mice. TN-C may thus accelerate adverse ventricular remodeling, cardiac failure, and fibrosis in the residual myocardium after MI..
72. Dong Yun Zhan, Sachio Morimoto, Cheng Kun Du, Yuan Yuan Wang, Qun Wei Lu, Atsushi Tanaka, Tomomi Ide, Yoshikazu Miwa, Fumi Takahashi, Toshiyuki Sasaguri, Therapeutic effect of β-adrenoceptor blockers using a mouse model of dilated cardiomyopathy with a troponin mutation, Cardiovascular research, 10.1093/cvr/cvp168, 84, 1, 64-71, 2009.10, AimsExtensive clinical studies have demonstrated that β-adrenoceptor blocking agents (β-blockers) are beneficial in the treatment of chronic heart failure, which is due to various aetiologies, including idiopathic dilated cardiomyopathy (DCM) and ischaemic heart disease. However, little is known about the therapeutic efficacy of β-blockers in the treatment of the inherited form of DCM, of which causative mutations have recently been identified in various genes, including those encoding cardiac sarcomeric proteins. Using a mouse model of inherited DCM with a troponin mutation, we aim to study the treatment benefits of β-blockers.Methods and resultsThree different types of β-blockers, carvedilol, metoprolol, and atenolol, were orally administered to a knock-in mouse model of inherited DCM with a deletion mutation ΔK210 in the cardiac troponin T gene (TNNT2). Therapeutic effects were examined on the basis of survival and myocardial remodelling. The lipophilic β1-selective β-blocker metoprolol was found to prevent cardiac dysfunction and remodelling and extend the survival of knock-in mice. Conversely, both the non-selective β-blocker carvedilol and the hydrophilic β1-selective β-blocker atenolol had no beneficial effects on survival and myocardial remodelling in this mouse model of inherited DCM.ConclusionThe highly lipophilic β1-selective β-blocker metoprolol, known to prevent ventricular fibrillation via central nervous system-mediated vagal activation, may be especially beneficial to DCM patients showing a family history of frequent sudden cardiac death, such as those with a deletion mutation ΔK210 in the TNNT2 gene..
73. Sanae Hamaguchi, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Takashi Yokota, Tomomi Ide, Akira Takeshita, Hiroyuki Tsutsui, Chronic kidney disease as an independent risk for long-term adverse outcomes in patients hospitalized with heart failure in Japan - Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), Circulation Journal, 10.1253/circj.CJ-09-0062, 73, 8, 1442-1447, 2009.08, Background: Previous studies have demonstrated that renal dysfunction is common in patients with heart failure (HF), but it is not known whether chronic kidney disease (CKD) is associated with increased risks of long-term adverse outcomes in unselected HF patients encountered in current routine clinical practice in Japan. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied a broad sample of patients hospitalized with worsening HF and their outcomes with an average of 2.4 years of follow-up. The study cohort (n=2,013) were classified into 3 groups by estimated glomerular filtration rate (eGFR): ≥60 (n=579), 30-59 (n=1,025), and <30ml·min-1·1.73 m-2 or patients with dialysis (n=409); 1,372 patients (70.3%) had an eGFR <60 ml·min-1·1.73 m-2 and 62 patients were treated with dialysis. The multivariable adjusted risk for all-cause death or rehospitalization increased with reduced eGFR; an adjusted hazard ratio (HR) 1.520 (95% confidence interval (CI) 1.186-1.949) for eGFR 30-59 ml·min-1·1.73 m-2 (P=0.001) and HR 2.566 (95%CI 1.885-3.492) for eGFR <30 ml·min-1·1.73 m-2 or patients with dialysis (P<0.001). Conclusions: CKD is common in HF and was independently associated with long-term adverse outcomes in a broad cohort of Japanese patients..
74. Jaakko L.O. Pohjoismäki, Steffi Goffart, Henna Tyynismaa, Smaranda Willcox, Tomomi Ide, Dongchon Kang, Anu Suomalainen, Pekka J. Karhunen, Jack D. Griffith, Ian J. Holt, Howard T. Jacobs, Human heart mitochondrial DNA is organized in complex catenated networks containing abundant four-way junctions and replication forks, Journal of Biological Chemistry, 10.1074/jbc.M109.016600, 284, 32, 21446-21457, 2009.08, Analysis of human heart mitochondrial DNA (mtDNA) by electron microscopy and agarose gel electrophoresis revealed a complete absence of the θ-type replication intermediates seen abundantly in mtDNA from all other tissues. Instead only Y- and X-junctional forms were detected after restriction digestion. Uncut heart mtDNA was organized in tangled complexes of up to 20 or more genome equivalents, which could be resolved to genomic monomers, dimers, and linear fragments by treatment with the decatenating enzyme topoisomerase IV plus the cruciform-cutting T7 endonuclease I. Human and mouse brain also contained a population of such mtDNA forms, which were absent, however, from mouse, rabbit, or pig heart. Overexpression in transgenic mice of two proteins involved in mtDNA replication, namely human mitochondrial transcription factor A or the mouse Twinkle DNA helicase, generated abundant four-way junctions in mtDNA of heart, brain, and skeletal muscle. The organization of mtDNA of human heart as well as of mouse and human brain in complex junctional networks replicating via a presumed non-θ mechanism is unprecedented in mammals..
75. Pohjoismäki JL, Goffart S, Tyynismaa H, Willcox S, Ide T, Kang D, Suomalainen A, Karhunen PJ, Griffith JD, Holt IJ, Jacobs HT., Human heart mitochondrial DNA is organized in complex catenated networks containing abundant four-way junctions and replication forks., J Biol Chem. , 284, 32, 21446-21457, 2009.06.
76. Inoue T, Ide T, Yamato M, Yoshida M, Tsutsumi T, Andou M, Utsumi H, Tsutsui H, Sunagawa K. , Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction. Free Radical Res 43: 37-46 (2009), Free Radical Res., 43, 37-46, 2009.05.
77. Takahiro Inoue, Tomomi Ide, Mayumi Yamato, Masayoshi Yoshida, Takaki Tsutsumi, Makoto Andou, Hideo Utsumi, Hiroyuki Tsutsui, Kenji Sunagawa, Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction, Free Radical Research, 10.1080/10715760802534820, 43, 1, 37-46, 2009.04, Reactive oxygen species (ROS) is increased in myocardium after myocardial infarction (MI), which may play a causal role in cardiac remodelling. However, there is scant direct and longitudinal evidence that systemic oxidative stress is enhanced accompanying an increase of ROS in myocardium. The authors conducted a comprehensive investigation of ROS markers by simultaneously sampling urine, blood and myocardium and in vivo ESR for the heart at different stages of post-MI cardiac remodelling in mouse with permanent occlusion of left coronary artery. Systemic oxidative markers increased at early days after MI and were normalized later. In contrast, TBARS and 4-hexanoyl-Lys staining were increased in non-infarct myocardium at day 28. The enhancement of ESR signal decay of methoxycarbonyl-PROXYL measured at the chest was associated with the progression of left ventricle dilatation and dysfunction. This study provided the direct evidence that redox alteration and production of ROS occurred in myocardium during the progression of cardiac remodelling and failure; however, ROS marker levels in blood and urine do not reflect the production of ROS from failing myocardium..
78. Inoue T, Ide T, Yamato M, Yoshida M, Tsutsumi T, Andou M, Utsumi H, Tsutsui H, Sunagawa K, Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction, Free radical research, 2009.01.
79. Motohiro Nishida, Yoji Sato, Aya Uemura, Yusuke Narita, Hidetoshi Saitoh, Nakaya Michio, Tomomi Ide, Kazuhiro Suzuki, Kazuhide Inoue, Taku Nagao, Hitoshi Kurose, P2Y6 receptor-Gα12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis, EMBO Journal, 10.1038/emboj.2008.237, 27, 23, 3104-3115, 2008.12, Cardiac fibrosis, characterized by excessive deposition of extracellular matrix proteins, is one of the causes of heart failure, and it contributes to the impairment of cardiac function. Fibrosis of various tissues, including the heart, is believed to be regulated by the signalling pathway of angiotensin II (Ang II) and transforming growth factor (TGF)-β. Transgenic expression of inhibitory polypeptides of the heterotrimeric G12 family G protein (Gα12/13) in cardiomyocytes suppressed pressure overload-induced fibrosis without affecting hypertrophy. The expression of fibrogenic genes (TGF-β, connective tissue growth factor, and periostin) and Ang-converting enzyme (ACE) was suppressed by the functional inhibition of Gα12/13. The expression of these fibrogenic genes through Gα12/13 by mechanical stretch was initiated by ATP and UDP released from cardiac myocytes through pannexin hemichannels. Inhibition of G-protein-coupled P2Y6 receptors suppressed the expression of ACE, fibrogenic genes, and cardiac fibrosis. These results indicate that activation of Gα12/13 in cardiomyocytes by the extracellular nucleotides-stimulated P2Y6 receptor triggers fibrosis in pressure overload-induced cardiac fibrosis, which works as an upstream mediator of the signalling pathway between Ang II and TGF-β..
80. Nozoe M, Hirooka Y, Koga Y, Araki S, Konno S, Kishi T, Ide T, Sunagawa K, Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla., Journal of Hypertension, 26; 2176-84, 2008.11.
81. Masatsugu Nozoe, Yoshitaka Hirooka, Yasuaki Koga, Shuichiro Araki, Satomi Konno, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla, Journal of hypertension, 10.1097/HJH.0b013e32830dd5d3, 26, 11, 2176-2184, 2008.11, OBJECTIVES: Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation. METHODS: In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production. RESULTS: Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca with ethylene glycol bis-N,N,N′,N′-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. CONCLUSION: These results indicate that AngII increases the intracellular Ca concentration and that the increase in mitochondrial Ca uptake leads to mitochondrial ROS production..
82. Takaki Tsutsumi, Tomomi Ide, Mayumi Yamato, Makoto Andou, Takeshi Shiba, Hideo Utsumi, Kenji Sunagawa, Effect of anaesthesia-induced alterations in haemodynamics on in vivo kinetics of nitroxyl probes in electron spin resonance spectroscopy, Free Radical Research, 10.1080/10715760801986542, 42, 4, 305-311, 2008.09, Although the advent of in vivo electron spin resonance (ESR) spectroscopy has allowed analysis of the redox status of living animals, whether the haemodynamic condition affects the signal decay rate remains unknown. Three kinds of haemodynamic conditions were generated by changing the anaesthetic dosage in mice. Haemodynamics was analysed (n = 6 each) and in vivo ESR was performed to measure the signal decay rates of three nitroxyl spin probes (carbamoyl-, carboxy- and methoxycarbonyl-PROXYL) at the chest and head regions (n = 6 for each condition and probe). Haemodynamic analysis revealed negative inotropic and chronotropic effects on the cardiovascular system depending on the depth of anaesthesia. Although signal decay rates differed among three probes, they were not affected by heart rate alteration. In this study we report the haemodynamics-independent signal decay rate of nitoxyl probes..
83. Hayashi Y, Yoshida M, Yamato M, Ide T, Wu Z, Ochi-Shindou M, Kanki T, Kang D, Sunagawa K, Tsutsui H, Nakanishi H, Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice, Journal of Neuroscience, 28: 8624-34, 2008.08.
84. Yoshinori Hayashi, Masayoshi Yoshida, Mayumi Yamato, Tomomi Ide, Hiro Take, Mayumi Ochi-Shindou, Tomotake Kanki, Dongchon Kang, Kenji Sunagawa, Hiroyuki Tsutsui, Hiroshi Nakanishi, Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor A in mice, Journal of Neuroscience, 10.1523/JNEUROSCI.1957-08.2008, 28, 34, 8624-8634, 2008.08, Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-κB (nuclear factor-κB) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1β (IL-1β) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1β amount markedly increased in the brain of the TG mice after treatment with lipopolysaccharide (LPS), whereas its mean amount was significantly lower than that of the LPS-treated aged wild-type mice. At the same time, an increased mtDNA damage in microglia and an impaired hippocampal LTP were also observed in the LPS-treated aged TG mice. Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia..
85. Fatty acids increase the circulating levels of oxidative stress factors in mice with diet-induced obesity via redox changes of albumin.
86. Tsutsumi T., Ide T., Yamato M., Andou M., Shiba T., Utsumi H., Sunagawa K, Effect of anaesthesia-induced alterations in haemodynamics on in vivo kinetics of nitroxyl probes in electron spin resonance spectroscopy., Free Radic Res., 305-311, 2008.04.
87. Tsutsumi T, Ide T, Yamato M, Kudou W, Andou M, Hirooka Y, Utsumi H, Tsutsui H, Sunagawa K, Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction., Cardiovasc Res., 713-721, 2008.03.
88. Takaki Tsutsumi, Tomomi Ide, Mayumi Yamato, Wataru Kudou, Makoto Andou, Yoshitaka Hirooka, Hideo Utsumi, Hiroyuki Tsutsui, Kenji Sunagawa, Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction, Cardiovascular research, 10.1093/cvr/cvm092, 77, 4, 713-721, 2008.03, Aims: Redox alteration plays a major role in the pathogenesis of heart failure (HF). Since vagal nerve stimulation (VNS) is known to improve survival and attenuate cardiac remodelling, we hypothesized that VNS may modulate the myocardial redox state. Methods and results: Using a chronic HF mouse model, we applied VNS for 15 min and measured myocardial redox status using in vivo electron spin resonance spectroscopy. Signal decay rate of the nitroxyl probe, an index of redox status, was enhanced in HF compared with sham (0.16 ± 0.01 vs. 0.13 ± 0.01 min-1, P < 0.05; n = 6), and VNS normalized this enhancement (0.13 ± 0.01 min-1, P < 0.05). Atropine sulphate abolished the VNS effects, indicating that the VNS modulates myocardial redox state via muscarinic receptors. Nω-Nitro-L- arginine methyl ester treatment and fixed-rate atrial pacing showed a trend to suppress the VNS effects, suggesting the involvement of nitric oxide-based signalling and myocardial oxygen consumption. Moreover, VNS decreased the myocardial norepinephrine (NE) level (0.25 ± 0.07 vs. 0.60 ± 0.12 ng/mL, P < 0.05; n = 6). Reactive oxygen species production from cultured cardiomyocytes was enhanced by β-adrenergic activation, which was partially antagonized by 10 μmol/L acetylcholine (ACh) (relative value compared with control: NE 3.7 ± 0.5, NE + ACh 2.5 ± 0.3, P < 0.05; n = 12). Conclusion: The present study suggests that VNS modulates the cardiac redox status and adrenergic drive, and thereby suppresses free radical generation in the failing heart..
89. Mayumi Yamato, Takeshi Shiba, Masayoshi Yoshida, Tomomi Ide, Naoko Seri, Wataru Kudou, Shintaro Kinugawa, Hiroyuki Tsutsui, Fatty acids increase the circulating levels of oxidative stress factors in mice with diet-induced obesity via redox changes of albumin, FEBS Journal, 10.1111/j.1742-4658.2007.05914.x, 274, 15, 3855-3863, 2007.08, Plasma concentrations of free fatty acids are increased in metabolic syndrome, and the increased fatty acids may cause cellular damage via the induction of oxidative stress. The present study was designed to determine whether the increase in fatty acids can modify the free sulfhydryl group in position 34 of albumin (Cys34) and enhance the redox-cycling activity of the copper-albumin complex in high-fat diet-induced obese mice. The mice were fed with commercial normal diet or high-fat diet and water ad libitum for 3 months. The high-fat diet-fed mice developed obesity, hyperlipemia, and hyperglycemia. The plasma fatty acid/albumin ratio also significantly increased in high-fat diet-fed mice. The increased fatty acid/albumin ratio was associated with conformational changes in albumin and the oxidation of sulfhydryl groups. Moreover, an ascorbic acid radical, an index of redox-cycling activity of the copper-albumin complex, was detected only in the plasma from obese mice, whereas the plasma concentrations of ascorbic acid were not altered. Plasma thiobarbituric acid reactive substances were significantly increased in the high-fat diet group. These results indicate that the increased plasma fatty acids in the high-fat diet group resulted in the activated redox cycling of the copper-albumin complex and excessive lipid peroxidation..
90. Yoshiya Monden, Toru Kubota, Takahiro Inoue, Takaki Tsutsumi, Shunichi Kawano, Tomomi Ide, Hiroyuki Tsutsui, Kenji Sunagawa, Tumor necrosis factor-α is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00166.2007, 293, 1, 2007.07, Tumor necrosis factor (TNF)-α induced in damaged myocardium has been considered to be cardiotoxic. TNF-α initiates its biological effects by binding two distinct receptors: R1 (p55) and R2 (p75). Although TNF-α has been shown to be cardiotoxic via R1-mediated pathways, little is known about the roles of R2-mediated pathways in myocardial infarction (MI). We created MI in R1 knockout (R1KO), R2KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 wk after ligation. Although infarct size was not different among WT, R1KO, and R2KO mice, post-MI survival was significantly improved in R1KO but not R2KO mice. R1KO significantly ameliorated contractile dysfunction after MI, whereas R2KO significantly exaggerated ventricular dilatation and dysfunction. Myocyte hypertrophy and interstitial fibrosis in noninfarct myocardium was exacerbated in R2KO but not in R1KO mice. Expression of R1, which was not affected by MI and was nullified in R1KO mice, was significantly upregulated in R2KO mice. In contrast, expression of R2, which was significantly upregulated by MI and was nullified in R2KO mice, was unaffected in R1KO mice. Meanwhile, TNF-α expression, which was significantly upregulated in noninfarct myocardium after MI, was not affected by R1KO or R2KO. However, transcript levels of IL-6, IL-1β, transforming growth factor-β, and monocyte chemotactic protein-1, which were significantly upregulated after MI, were significantly downregulated in R1KO mice. In contrast, transcript levels of IL-6 and IL-1β were significantly further upregulated in R2KO mice. TNF-α is toxic via R1 and protective via R2 in a murine model of MI. Selective blockade of R1 may be a candidate therapeutic intervention for MI..
91. Tsutsui H, Matsushima S, Kinugawa S, Ide T, Inoue N, Ohta Y, Yokota T Hamaguchi S, Sunagawa K, Angiotensin II type 1 receptor blocker attenuates myocardial remodeling and preserves diastolic function in diabetic heart., Hypertension Res, 439-449, 2007.05.
92. Tsutsui H, Matsushima S, Kinugawa S, Ide T, Inoue N, Ohta Y, Yokota T, Hamaguchi S, Sunagawa K., Angiotensin II type 1 receptor blocker attenuates myocardial remodeling and preserves diastolic function in diabetic heart., 30(5):439-49., 2007.05.
93. Hiroyuki Tsutsui, Shoji Matsushima, Shintaro Kinugawa, Tomomi Ide, Naoki Inoue, Yukihiro Ohta, Takashi Yokota, Sanae Hamaguchi, Kenji Sunagawa, Angiotensin II type 1 receptor blocker attenuates myocardial remodelling and preserves diastolic function in diabetic heart, Hypertension Research, 10.1291/hypres.30.439, 30, 5, 439-449, 2007.05, Blockade of the renin-angiotensin system reduces cardiovascular morbidity and mortality in diabetic patients. Angiotensin II (Ang II) plays an important role in the structural and functional abnormalities of the diabetic heart. We investigated whether or not Ang II type 1 receptor blocker (ARB) could attenuate left ventricular (LV) remodeling in male mice with diabetes mellitus (DM) induced by the injection of streptozotocin (200 mg/kg, i.p.). Diabetic mice were treated with candesartan (1 mg/kg/day; DM+Candesartan, n=7) or vehicle (DM+Vehicle, n=7) for 8 weeks. Heart rate and aortic blood pressure were comparable between the groups. Normal systolic function was preserved in diabetic mice. In contrast diastolic function was impaired in DM+Vehicle and was improved in DM+Candesartan, as assessed by the deceleration time of the peak velocity of transmitral diastolic flow (40.3±0.3 vs. 37.3±0.5 ms, p<0.01) and the time needed for relaxation of 50% maximal LV pressure to baseline value (τ; 10.6±0.7 vs. 8.7±0.6 ms, p<0.05) without significant changes in heart rate and aortic blood pressure. Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis and apoptosis in association with the expression of connective tissue growth factor (CTGF) and myocardial oxidative stress. Moreover, candesartan directly inhibited Ang II-mediated Induction of CTGF in cultured cardiac fibroblasts. ARB might be beneficial to prevent cardiac abnormalities in DM..
94. Yoshiya Monden, Toru Kubota, Takaki Tsutsumi, Takahiro Inoue, Shunichi Kawano, Natsumi Kawamura, Tomomi Ide, Kensuke Egashira, Hiroyuki Tsutsui, Kenji Sunagawa, Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction, Cardiovascular research, 10.1016/j.cardiores.2006.12.016, 73, 4, 794-805, 2007.03, Objective: Tumor necrosis factor (TNF)-α induced in damaged myocardium has been considered to be cardiotoxic. However, the negative results of RENEWAL and ATTACH prompt us to reconsider the role of TNF-α in cardiovascular diseases. The present study aimed to evaluate the effects of soluble TNF receptor treatment on myocardial infarction (MI). Methods: An adenovirus encoding a 55-kDa TNF receptor-IgG fusion protein (AdTNFR1) was used to neutralize TNF-α, and an adenovirus encoding LacZ (AdLacZ) served as control. In the pre-MI treatment protocol, mice were given an intravenous injection of AdTNFR1 or AdLacZ 1 week before left coronary artery ligation to induce MI. In the post-MI treatment protocol, mice were treated with AdTNFR1 or AdLacZ 1 week after left coronary ligation. Results: Treatment with AdTNFR1 neutralized bioactivity of TNF-α that was activated after MI and prevented apoptosis of infiltrating cells in infarct myocardium. However, pre-MI treatment with AdTNFR1 promoted ventricular rupture by reducing fibrosis with further activation of matrix metalloproteinase (MMP)-9. Post-MI treatment with AdTNFR1 exacerbated ventricular dysfunction and remodeling, with enhanced fibrosis of non-infarct myocardium with further MMP-2 activation. Conclusions: Both pre- and post-MI treatments with AdTNFR1 were deleterious in a mouse MI model. Thus, TNF-α may play not only toxic but also protective roles in MI..
95. Tomomi Ide, Kenji Sunagawa, Diuretics--character, mechanisms, indications, side effects, Nippon rinsho. Japanese journal of clinical medicine, 65 Suppl 5, 34-38, 2007.01.
96. Tomomi Ide, Kenji Sunagawa, ROS and disorder of mitochondrial DNA, Nippon rinsho. Japanese journal of clinical medicine, 65 Suppl 4, 238-242, 2007.01.
97. Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart..
98. Shoji Matsushima, Shintaro Kinugawa, Tomomi Ide, Hidenori Matsusaka, Naoki Inoue, Yukihiro Ohta, Takashi Yokota, Kenji Sunagawa, Hiroyuki Tsutsui, Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00427.2006, 291, 5, 2006.11, Oxidative stress plays an important role in the structural and functional abnormalities of diabetic heart. Glutathione peroxidase (GSHPx) is a critical antioxidant enzyme that removes H2O2 in both the cytosol and mitochondia. We hypothesized that the overexpression of GSHPx gene could attenuate left ventricular (LV) remodeling in diabetes mellitus (DM). We induced DM by injection of streptozotocin (160 mg/kg ip) in male GSHPx transgenic mice (TG+DM) and nontransgenic wildtype littermates (WT+DM). GSHPx activity was higher in the hearts of TG mice compared with WT mice, with no significant changes in other antioxidant enzymes. LV thiobarbituric acid-reactive substances measured in TG+DM at 8 wk were significantly lower than those in WT+DM (58 ± 3 vs. 71 ± 5 nmol/g, P < 0.05). Heart rate and aortic blood pressure were comparable between groups. Systolic function was preserved normal in WT+DM and TG+DM mice. In contrast, diastolic function was impaired in WT+DM and was improved in TG+DM as assessed by the deceleration time of peak velocity of transmitral diastolic flow and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 13.5 ± 1.2 vs. 8.9 ± 0.7 ms, P < 0.01). The TG+DM values were comparable with those of WT+Control (tau; 7.8 ± 0.2 ms). Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis, and apoptosis. Overexpression of GSHPx gene ameliorated LV remodeling and diastolic dysfunction in DM. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac abnormalities in DM..
99. Tsutsui H, Ide T, Kinugawa S., Mitochondrial oxidative stress, DNA damage, and heart failure, Antioxid Redox Signal. , 8(9-10):1737-44., 2006.09.
100. Hidenori Matsusaka, Shintaro Kinugawa, Tomomi Ide, Shoji Matsushima, Tetsuya Shiomi, Toru Kubota, Kenji Sunagawa, Hiroyuki Tsutsui, Angiotensin II type 1 receptor blocker attenuates exacerbated left ventricular remodeling and failure in diabetes-associated myocardial infarction, Journal of Cardiovascular Pharmacology, 10.1097/01.fjc.0000245405.41317.60, 48, 3, 95-102, 2006.09, Diabetes mellitus adversely affects the outcomes in patients with myocardial infarction (MI), due in part to the exacerbation of left ventricular (LV) remodeling. Although angiotensin II type 1 receptor blocker (ARB) has been demonstrated to be effective in the treatment of heart failure, information about the potential benefits of ARB on advanced LV failure associated with diabetes is lacking. To induce diabetes, male mice were injected intraperitoneally with streptozotocin (200 mg/kg). At 2 weeks, anterior MI was created by ligating the left coronary artery. These animals received treatment with olmesartan (0.1 mg/kg/day; n = 50) or vehicle (n = 51) for 4 weeks. Diabetes worsened the survival and exaggerated echocardiographic LV dilatation and dysfunction in MI. Treatment of diabetic MI mice with olmesartan significantly improved the survival rate (42% versus 27%, P < 0.05) without affecting blood glucose, arterial blood pressure, or infarct size. It also attenuated LV dysfunction in diabetic MI. Likewise, olmesartan attenuated myocyte hypertrophy, interstitial fibrosis, and the number of apoptotic cells in the noninfarcted LV from diabetic MI. Post-MI LV remodeling and failure in diabetes were ameliorated by ARB, providing further evidence that angiotensin II plays a pivotal role in the exacerbated heart failure after diabetic MI..
101. Hiroyuki Tsutsui, Tomomi Ide, Shintaro Kinugawa, Mitochondrial oxidative stress, DNA damage, and heart failure, Antioxidants and Redox Signaling, 10.1089/ars.2006.8.1737, 8, 9-10, 1737-1744, 2006.09, Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart, whereas antioxidant enzyme activities are preserved as normal. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target of oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, mitochondrial oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number and preserve it at a normal level in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities was also prevented. Therefore, the activation of TFAM expression could ameliorate the pathophysiologic processes seen in myocardial failure. Inhihition of mitochondrial oxidative stress and mtDNA damage could be novel and potentially very effective treatment strategies for heart failure..
102. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H., Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice., Cardiovasc Res. , 70(3):457-65. , 2006.06.
103. Hidenori Matsusaka, Tomomi Ide, Shoji Matsushima, Masaki Ikeuchi, Toru Kubota, Kenji Sunagawa, Shintaro Kinugawa, Hiroyuki Tsutsui, Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice, Cardiovascular research, 10.1016/j.cardiores.2006.02.001, 70, 3, 457-465, 2006.06, Objective: Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts. Methods: Anterior MI was created in male heterozygous p53-deficient (p53+/-; n = 28) mice and sibling wild-type (p53+/+; n = 29) mice by ligating the left coronary artery. Results: By day 7, p53+/- mice had significantly better survival rate than p53+/+ mice (89% vs. 69%, P < 0.05). Notably, p53+/- mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 ± 2% vs. 59 ± 2%, P = NS), heart rate (488 ± 15 vs. 489 ± 17 bpm, P = NS), or mean arterial blood pressure (80 ± 2 vs. 78 ± 3 mm Hg, P = NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53+/- and p53+/+ mice with MI. However, the p53+/- mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53+/- mice than in p53+/+ mice (423 ± 86 vs. 1330 ± 275/105 cells, P < 0.01). Conclusions: p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients..
104. Matsushima S, Ide T, Yamato M, Matsusaka H, Hattori F, Ikeuchi M, Kubota T, Sunagawa K, Hasegawa Y, Kurihara T, Oikawa S, Kinugawa S, Tsutsui H., Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice., Circulation, 113(14):1779-86., 2006.04.
105. Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload..
106. Shoji Matsushima, Tomomi Ide, Mayumi Yamato, Hidenori Matsusaka, Fumiyuki Hattori, Masaki Ikeuchi, Toru Kubota, Kenji Sunagawa, Yasuhiro Hasegawa, Tatsuya Kurihara, Shinzo Oikawa, Shintaro Kinugawa, Hiroyuki Tsutsui, Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice, Circulation, 10.1161/CIRCULATIONAHA.105.582239, 113, 14, 1779-1786, 2006.04, BACKGROUND - Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process. METHODS AND RESULTS - We created MI in 12- to 16-week-old, male Prx-3-transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid-reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean±SEM, 1.5±0.2 vs 2.2±0.2 nmol/mg protein; n=8 each, P<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56±1% vs 55±1%; n=6 each, P=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice. CONCLUSIONS - Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure..
107. Hidenori Matsusaka, Tomomi Ide, Shoji Matsushima, Masaki Ikeuchi, Toru Kubota, Kenji Sunagawa, Shintaro Kinugawa, Hiroyuki Tsutsui, Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload, Hypertension, 10.1161/01.HYP.0000208840.30778.00, 47, 4, 711-717, 2006.04, Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2±0.2 versus 5.0±0.2 mg/g; P<0.01), lung weight/body weight (4.9±0.2 versus 6.2±0.4 mg/g; P<0.01), and LV end-diastolic pressure (4±1 versus 10±2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322±14 versus 392±14 μm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3±0.5 versus 8.2±1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease..
108. Tomomi Ide, Seeking for the endogenous ligands for PPARγ, Journal of Clinical Biochemistry and Nutrition, 10.3164/jcbn.37.39, 37, 2, 39-44, 2005.12, Peroxisome proliferators-activated receptors gamma (PPARγ) is an isoform of PPARs which are members of the nuclear receptor superfamily and are considered as key sensors of lipid and glucose homeostasis. This ligand-activated transcription factor has been intensively studied for more than a decade and the bona fide endogenous ligand remains unknown. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ 2) is of great interest because it affects gene transcription by binding and activating PPARγ and by covalent addition to transcription factors and signaling molecules. However, the actual concentration of 15d-PGJ2 is several orders of magnitude below the levels required to induce many of the biological reaction attributed to this molecule. This short review will focus on 15d-PGJ2 as a ligand of PPARγ and on other candidates of the endogenous ligand for the receptor..
109. Matsusaka H, Ikeuchi M, Matsushima S, Ide T, Kubota T, Feldman AM, Takeshita A, Sunagawa K, Tsutsui H., Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy., Am J Physiol Heart Circ Physiol. , 10.1152/ajpheart.00216.2005, 289, 5, H1858-H1864, 289(5):H1858-64. , 2005.11.
110. Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T, Kubota T, Fujiwara T, Hamasaki N, Takeshita A, Sunagawa K, Tsutsui H., Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction., Circulation., 10.1161/CIRCULATIONAHA.104.524835, 112, 5, 683-690, 112(5):683-90. , 2005.08.
111. Ide T, Bell-Parikh LC, Lawson JA, McNamara P, Reilly M, FitzGerald GA., Biosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPARgamma., J Clin Invest. , 112(6):945-55., 2003.09.
112. Ide T, Egan K, Bell-Parikh LC, FitzGerald GA., Activation of nuclear receptors by prostaglandins., Thromb Res. , 110(5-6):311-5., 2003.06.
113. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes..
114. Machida Y, Kubota T, Kawamura N, Funakoshi H, Ide T, Utsumi H, Li YY, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A., Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium., Am J Physiol Heart Circ Physiol., 10.1152/ajpheart.00581.2002, 284, 2, H449-H455, 284(2):H449-55. , 2003.02.
115. Yoji Machida, Toru Kubota, Natsumi Kawamura, Hajime Funakoshi, Tomomi Ide, Hideo Utsumi, Yun You Li, Arthur M. Feldman, Hiroyuki Tsutsui, Hiroaki Shimokawa, Akira Takeshita, Overexpression of tumor necrosis factor-α increases production of hydroxyl radical in murine myocardium, American Journal of Physiology - Heart and Circulatory Physiology, 284, 2 53-2, 2003.02, Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-α develop congestive heart failure with myocardial inflammation. The purpose of this study was to investigate the effects of tumor necrosis factor-α on reactive oxygen species (ROS) in this mouse model of cardiomyopathy. Myocardial production of hydroxyl radical detected by electron spin resonance spectroscopy was significantly increased in TG. Myocardial expression of Mn-SOD was significantly decreased in TG, whereas that of Cu,Zn-SOD was unaltered. Myocardial expression of catalase was unchanged, whereas that of glutathione peroxidase was significantly increased, in TG. Histological analysis revealed that macrophages and CD4-positive lymphocytes were increased in TG myocardium. To investigate whether these infiltrating inflammatory cells were the source of ROS, we treated TG mice with cyclophosphamide for 7 days. Although cyclophosphamide significantly suppressed the infiltration of inflammatory cells, it did not diminish the production of hydroxyl radical in TG myocardium. Damaged myocytes, but not infiltrating inflammatory cells, may be the source of ROS in TG..
116. Hiroyuki Tsutsui, Tomomi Ide, Akira Takeshita, Noriko Ohashi, Physiological variations of isoprostanes
A step forward? Response to letter to the editor [3], Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 7, 1240-1241, 2002.07.
117. Ide T, Tsutsui H, Ohashi N, Hayashidani S, Suematsu N, Tsuchihashi M, Tamai H, Takeshita A., Greater oxidative stress in healthy young men compared with premenopausal women., Arterioscler Thromb Vasc Biol. , 10.1161/hq0302.104515, 22, 3, 438-442, 22(3):438-42., 2002.03.
118. Hayashidani S, Tsutsui H, Shiomi T, Suematsu N, Kinugawa S, Ide T, Wen J, Takeshita A., Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction., Circulation. , 10.1161/hc0702.104164, 105, 7, 868-873, 2002 Feb 19;105(7):868-73., 2002.02.
119. Tsutsui H, Ide T, Shiomi T, Kang D, Hayashidani S, Suematsu N, Wen J, Utsumi H, Hamasaki N, Takeshita A., 8-oxo-dGTPase, which prevents oxidative stress-induced DNA damage, increases in the mitochondria from failing hearts., Circulation, 10.1161/hc4901.101347, 104, 24, 2883-2885, 104:2883-5., 2001.12.
120. Nakamura R, Egashira K, Arimura K, Machida Y, Ide T, Tsutsui H, Shimokawa H, Takeshita A., Increased inactivation of nitric oxide is involved in impaired coronary flow reserve in heart failure., Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2619-25., 281, 6, H2619-H2625, 281(6):H2619-25., 2001.12.
121. R. Y.O. Nakamura, Kensuke Egashira, Kenichi Arimura, Youji Machida, Tomomi Ide, Hiroyuki Tsutsui, Hiroaki Shimokawa, Akira Takeshita, Increased inactivation of nitric oxide is involved in impaired coronary flow reserve in heart failure, American Journal of Physiology - Heart and Circulatory Physiology, 281, 6 50-6, 2001.12, Recent evidence suggests that increased inactivation of endothelium-derived nitric oxide (NO) by oxygen free radical (OFR) formation is involved in the pathogenesis of endothelial dysfunction in heart failure (HF). However, it is unclear whether increased OFR limits coronary flow reserve in HF. To test this hypothesis, we examined the effects of antioxidant therapy on coronary flow reserve in a canine model of tachycardia-induced HF. The flow reserve (percent increase in coronary blood flow) to adenosine or to 20-s ischemia was less and OFR formation (electron-spin resonance spectroscopy) in myocardial tissues was greater in HF dogs than in controls. Immunohistochemical staining of 4-hydroxy-2-nonenal, an OFR-induced lipid peroxide, was detected in coronary microvessels of HF dogs. Intracoronary infusion of a cell-permeable OFR scavenger, tiron, suppressed OFR formation and improved the vasodilating capacity to adenosine or brief ischemia in HF dogs but not in controls. A NO synthesis inhibitor, NG-monomethyl-Larginine (L-NMMA), diminished the beneficial effects of tiron in HF dogs. Vasodilation to sodium nitroprusside was similar between control and HF dogs, and no change in its response was noted with tiron or tiron + L-NMMA in either group. In summary, antioxidant treatment with tiron improved coronary flow reserve by increasing NO bioactivity in HF dogs. Thus increased OFR formation may impair coronary flow reserve in HF by reducing NO bioactivity..
122. Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure..
123. Hiroyuki Tsutsui, Tomomi Ide, Shunji Hayashidani, Nobuhiro Suematsu, Tetsuya Shiomi, Jing Wen, Kei Ichiro Nakamura, Kazuhiro Ichikawa, Hideo Utsumi, Akira Takeshita, Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure, Circulation, 10.1161/01.CIR.104.2.134, 104, 2, 134-136, 2001.07, Background - The generation of reactive oxygen species (ROS) is enhanced in the failing myocardium. We hypothesized that ROS were also increased in the limb skeletal muscles in heart failure. Methods and Results - Myocardial infarction (MI) was created in mice by ligating the left coronary artery. After 4 weeks, the left ventricle was dilated and contractility was diminished by echocardiography. Left ventricular end-diastolic pressure was elevated after MI in association with an increase in lung weight/body weight and the presence of pleural effusion. The generation of ROS in the limb muscles, including the soleus and gastrocnemius muscles, which were excised after MI, was measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Overall, generation was increased, but it was attenuated in the presence of dimethylthiourea or 4,5-dihydroxy-1,2-benzenedisulfonic disodium salt in the reaction mixture, indicating increased generation of hydroxyl radicals originating from superoxide anion. Thiobarbituric acid-reactive substance formation was also increased in muscles after MI. Mitochondrial complex I and III activities were both decreased after MI, which may have caused the functional uncoupling of the respiratory chain and ROS production. Antioxidant enzyme activities, including superoxide dismutase, catalase, and glutathione peroxidase, were comparable between groups. Conclusions - Skeletal muscle in post-MI heart failure expressed an increased amount of ROS in association with ROS-mediated lipid peroxidation. This supports the hypothesis that oxidative stress may cause (at least in part) skeletal muscle dysfunction in heart failure..
124. Tsutsui H, Ide T, Hayashidani S, Kinugawa S, Suematsu N, Utsumi H, Takeshita A., Effects of ACE inhibition on left ventricular failure and oxidative stress in Dahl salt-sensitive rats.
, J Cardiovasc Pharmacol., 10.1097/00005344-200106000-00010, 37, 6, 725-733, 37(6):725-33., 2001.06.
125. Kenichi Akimura, Kensuke Egashira, Ryo Nakamura, Tomomi Ide, Hiroyuki Tsutsui, Hiroaki Shimokawa, Akira Takeshita, Increased inactivation of nitric oxide is involved in coronary endothelial dysfunction in heart failure, American Journal of Physiology - Heart and Circulatory Physiology, 280, 1 49-1, 2001.06, Recent evidence suggests the possibility that enhanced inactivation of endothelium-derived nitric oxide (NO) by oxygen free radical (OFR) may cause endothelial dysfunction in heart failure (HF). To test this hypothesis, we examined the effect of antioxidant therapy on endothelium-dependent vasodilation of the coronary circulation in a canine model of tachycardia-induced HF. Endothelium-dependent vasodilation was less than that in controls, and OFR formation in coronary arterial and myocardial tissues was greater in HF dogs than those in controls. The immunohistochemical staining of 4-hydroxy-2-nonenal, OFR-induced lipid peroxides was detected in coronary microvessels of HF dogs. Intracoronary infusion of the cell-permeable OFR scavenger Tiron inhibited OFR formation and improved endothelium-dependent vasodilation in HF dogs but not in controls. The NO synthesis inhibitor NG-monomethyl-L-arginine (L-NMMA) diminished the beneficial effect of Tiron in HF dogs. Endothelium-independent vasodilation was similar between control and HF dogs, and no change in its response was noted by Tiron or Tiron plus L-NMMA in either group. In summary, antioxidant treatment with Tiron improved coronary vascular endothelium-dependent vasodilation by increasing NO activity in tachycardia-induced HF. Thus coronary endothelial dysfunction in HF may be, at least in part, due to increased inactivation of NO by OFR..
126. Tomomi Ide, Hiroyuki Tsutsui, Shunji Hayashidani, Dongchon Kang, Nobuhiro Suematsu, Kei Ichiro Nakamura, Hideo Utsumi, Naotaka Hamasaki, Akira Takeshita, Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction, Circulation research, 10.1161/01.RES.88.5.529, 88, 5, 529-535, 2001.03, Mitochondria are one of the enzymatic sources of reactive oxygen species (ROS) and could also be a major target for ROS-mediated damage. We hypothesized that ROS may induce mitochondrial DNA (mtDNA) damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes and thus may contribute to the progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). In a murine model of MI and remodeling created by the left anterior descending coronary artery ligation for 4 weeks, the LV was dilated and contractility was diminished. Hydroxyl radicals, which originated from the superoxide anion, and lipid peroxide formation in the mitochondria were both increased in the noninfarcted LV from MI mice. The mtDNA copy number relative to the nuclear gene (18S rRNA) preferentially decreased by 44% in MI by a Southern blot analysis, associated with a parallel decrease (30% to 50% of sham) in the mtDNA-encoded gene transcripts, including the subunits of complex I (ND1, 2, 3, 4, 4L, and 5), complex III (cytochrome b), complex IV (cytochrome c oxidase), and rRNA (12S and 16S). Consistent with these molecular changes, the enzymatic activity of complexes I, III, and IV decreased in MI, whereas, in contrast, complex II and citrate synthase, encoded only by nuclear DNA, both remained at normal levels. An intimate link among ROS, mtDNA damage, and defects in the electron transport function, which may lead to an additional generation of ROS, might play an important role in the development and progression of LV remodeling and failure..
127. Tsutsui H, Kinugawa S, Ide T, Hayashidani S, Suematsu N, Satoh S, Nakamura R, Egashira K, Takeshita A., Positive inotropic effects of calcium sensitizers on normal and failing cardiac myocytes., JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 10.1097/00005344-200101000-00003, 37, 1, 16-24, 37(1):16-24., 2001.01.
128. Hiroyuki Tsutsui, Tomomi Ide, Shunji Hayashidani, Nobuhiro Suematsu, Hideo Utsumi, Ryo Nakamura, Kensuke Egashira, Akira Takeshita, Greater susceptibility of failing cardiac myocytes to oxygen free radical-mediated injury, Cardiovascular research, 10.1016/S0008-6363(00)00197-8, 49, 1, 103-109, 2001.01, Objective: Oxygen-derived free radicals can produce myocardial cellular damage, which might contribute to the ischemia-reperfusion injury and to heart failure (HF). However, the effects of oxygen radicals on myocyte structure have not been examined in the failing heart. Methods: We examined the susceptibility of intact cardiac myocytes isolated from control (n=16) and rapid pacing (240 bpm, 4 wks)-induced HF (n=8) dog hearts to an exogenous hydroxyl radical (·OH), generated from H2O2 and Fe3+-nitrilotriacetate. The production of ·OH was monitored by electron spin resonance with 5,5'-dimethyl-1-pyroline-N-oxide (DMPO) as a spin trap. Results: The magnitude of DMPO-OH signals was not attenuated in the presence of either control or HF myocytes. ·OH induced a time-dependent decrease in myocyte length (i.e. hypercontracture). The time to the onset of hypercontracture and that to the submaximal hypercontracture after exposure was significantly shortened in HF. Activities of superoxide dismutase, catalase, and glutathione peroxidase was not decreased in HF. Conclusions: HF myocytes were more susceptible to oxidative stress-induced cellular injury, which was not due to decreased antioxidant defense, but to the intrinsic properties of cells. (C) 2001 Elsevier Science B.V..
129. Shintaro Kinugawa, Hiroyuki Tsutsui, Shunji Hayashidani, Tomomi Ide, Nobuhiro Suematsu, Shinji Satoh, Hideo Utsumi, Akira Takeshita, Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice
Role of oxidative stress, Circulation research, 10.1161/01.RES.87.5.392, 87, 5, 392-398, 2000.09, Oxidative stress might play an important role in the progression of left ventricular (LV) remodeling and failure that occur after myocardial infarction (MI). We determined whether reactive oxygen species (ROS) are increased in the LV remodeling and failure in experimental MI with the use of electron spin resonance spectroscopy and whether the long-term administration of dimethylthiourea (DMTU), hydroxyl radical (.OH) scavenger, could attenuate these changes. We studied 3 groups of mice: sham-operated (sham), MI, and MI animals that received DMTU (MI+DMTU). Drugs were administered to the animals daily via intraperitoneal injection for 4 weeks. (.OH) was increased in the noninfarcted myocardium from MI animals, which was abolished in MI+DMTU. Fractional shortening was depressed by 65%, LV chamber diameter was increased by 53%, and the thickness of noninfarcted myocardium was increased by 37% in MI. MI+DMTU animals had significantly better LV contractile function and smaller increases in LV chamber size and hypertrophy than MI animals. Changes in myocyte cross-sectional area determined with LV mid-free wall specimens were concordant with the wall thickness data. Collagen volume fraction of the noninfarcted myocardium showed significant increases in the MI, which were also attenuated with DMTU. Myocardial matrix metalloproteinase-2 activity, measured with gelatin zymography, was increased with MI after 7 and 28 days, which was attenuated in MI+DMTU. Thus, the attenuation of increased myocardial ROS and metalloproteinase activity with DMTU may contribute, at least in part, to its beneficial effects on LV remodeling and failure. Therapies designed to interfere with oxidative stress might be beneficial to prevent myocardial failure..
130. Tomomi Ide, Hiroyuki Tsutsui, Shintaro Kinugawa, Nobuhiro Suematsu, Shunji Hayashidani, Kazuhiro Ichikawa, Hideo Utsumi, Youji Machida, Kensuke Egashira, Akira Takeshita, Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium, Circulation research, 10.1161/01.RES.86.2.152, 86, 2, 152-157, 2000.01, Experimental and clinical studies have suggested an increased production of reactive oxygen species (ROS) in the failing myocardium. The present study aimed to obtain direct evidence for increased ROS and to determine the contribution of superoxide anion (·O2-), H2O2, and hydroxy radical (·OH) in failing myocardial tissue. Heart failure was produced in adult mongrel dogs by rapid ventricular pacing at 240 bpm for 4 weeks. To assess the production of ROS directly, freeze-clamped myocardial tissue homogenates were reacted with the nitroxide radical, 4-hydroxy-2,2,6,6,-tetramethyl- piperidine-N-oxyl, and its spin signals were detected by electron spin resonance spectroscopy. The rate of electron spin resonance signal decay, proportional to ·OH level, was significantly increased in heart failure, which was inhibited by the addition of dimethylthiourea (·OH scavenger) into the reaction mixture. Increased ·OH in the failing heart was abolished to the same extent in the presence of desferrioxamine (iron chelator), catalase (H2O2 scavenger), and 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron; LaMotte) (·O2- scavenger), indicating that ·OH originated from H2O2 and ·O2-. Further, ·O2- produced in normal myocardium in the presence of antimycin A (mitochondrial complex III inhibitor) could reproduce the increase of H2O2 and ·OH seen in the failing tissue. There was a significant positive relation between myocardial ROS level and left ventricular contractile dysfunction. In conclusion, in the failing myocardium, ·OH was produced as a reactive product of ·O2- and H2O2, which might play an important role in left ventricular failure..
131. Shintaro Kinugawa, Hiroyuki Tsutsui, Shinji Satoh, Masaru Takahashi, Tomomi Ide, Keiko Igarashi-Saito, Ken ichi Arimura, Kensuke Egashira, Akira Takeshita, Role of Ca2+ availability to myofilaments and their sensitivity to Ca2+ in myocyte contractile dysfunction in heart failure, Cardiovascular research, 10.1016/S0008-6363(99)00205-9, 44, 2, 398-406, 1999.11, Objective: Contractile function is depressed at the isolated myocyte level in heart failure (HF), which could result from the decreased availability of intracellular calcium ([Ca2+]i) to the myofibrils and/or the depressed sensitivity of myofilaments to [Ca2+]i. However, the cellular basis of contractile dysfunction remains unestablished. Methods: We isolated left ventricular myocytes from dogs with rapid pacing-induced HF. Cell shortening and [Ca2+]i transients were measured by indo-1 fluorescence and the myofilament Ca2+ sensitivity was analyzed by the shortening-[Ca2+]i relation in intact myocytes as well as by the pCa-tension relation in skinned cells. Results: Peak cell shortening magnitude was depressed in HF, associated with a parallel decrease of [Ca2+]i transient amplitude. There was a significant positive correlation between these two variables (r=0.71, P<0.01). In contrast, myofibrillar sensitivity to Ca2+, determined by both intact and skinned myocytes, was comparable between control and HF. Further, there was no significant difference in Ca2+ sensitivity between control and HF even at shorter (1.8 μm) or longer (2.2 μm) sarcomere length. Conclusions: Using both intact and skinned cellular preparations, a potential defect in myocyte contractile function in HF was a reduction in Ca2+ availability to the myofilaments, rather than the inherent defects in myofilament sensitivity to Ca2+. Copyright (C) 1999 Elsevier Science B.V..
132. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Takeshita A., Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action., Circulation. , 100, 7, 690-692, 17;100(7):690-2., 1999.08.
133. Tomomi Ide, Hiroyuki Tsutsui, Shintaro Kinugawa, Hideo Utsumi, Akira Takeshita, Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action, Circulation, 100, 7, 690-692, 1999.08, Background-Oxidative stress plays an important role in the pathophysiology of ischemic heart disease and heart failure, and antioxidants might be beneficial in the treatment of these patients. This study was performed to determine the scavenging effects of amiodarone on oxygen free radicals and its protective effects against oxygen radical-mediated injury in cardiac myocytes. Methods and Results-The formation of the radical spin adduct with hydroxy radical (·OH) in the presence of H2O2 (10 mmol/L) and Fe3+-nitrilotriacetate (20 μmol/L) was monitored by electron paramagnetic resonance spectroscopy combined with a spin trapping agent, 5,5-dimethyl pyrroline-N-oxide (DMPO). Amiodarone decreased the intensity of the DMPO-OH signals in a dose-dependent manner (0.1 to 100 μmol/L), whereas other antiarrhythmia drugs such as disopyramide and atenolol had no such effects. Furthermore, amiodarone (10 μmol/L) protected intact adult canine cardiac myocytes against ·OH-mediated myocyte injury, as assessed by the degree of morphological change from rod shape to the irreversible hypercontracture state during the exposure of cells to H2O2 and Fe3+ in vitro. Conclusions-Amiodarone can protect cardiac myocytes against oxidative stress- mediated injury by directly scavenging oxygen free radicals. Antioxidant action of amiodarone might potentially contribute to the beneficial effects of this drug in the treatment of patients with ischemic heart disease and congestive heart failure..
134. Tomomi Ide, Hiroyuki Tsutsui, Shintaro Kinugawa, Hideo Utsumi, Dongchon Kang, Nobutaka Hattori, Koji Uchida, Ken Ichi Arimura, Kensuke Egashira, Akira Takeshita, Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium, Circulation research, 10.1161/01.RES.85.4.357, 85, 4, 357-363, 1999.08, Oxidative stress in the myocardium may play an important role in the pathogenesis of congestive heart failure (HF). However, the cellular sources and mechanisms for the enhanced generation of reactive oxygen species (ROS) in the failing myocardium remain unknown. The amount of thiobarbituric acid reactive substances increased in the canine HF hearts subjected to rapid ventricular pacing for 4 weeks, and immunohistochemical staining of 4- hydroxy-2-nonenal ROS-induced lipid peroxides was detected in cardiac myocytes but not in interstitial cells of HF animals. The generation of superoxide anion was directly assessed in the submitochondrial fractions by use of electron spin resonance spectroscopy with spin trapping agent, 5,5'- dimethyl-1-pyrroline-N-oxide, in the presence of NADH and succinate as a substrate for NADH-ubiquinone oxidoreductase (complex I) and succinate- ubiquinone oxidoreductase (complex II), respectively. Superoxide production was increased 2.8-fold (P<0.01) in HF, which was due to the functional block of electron transport at complex I. The enzymatic activity of complex I decreased in HF (274±13 versus 136±9 nmol · min-1· mg-1 protein, P<0.01), which may thus have caused the functional uncoupling of the respiratory chain and the deleterious ROS production in HF mitochondria. The present study provided direct evidence for the involvement of ROS in the mitochondrial origin of HF myocytes, which might be responsible for both contractile dysfunction and structural damage to the myocardium..
135. Shintaro Kinugawa, Hiroyuki Tsutsui, Tomomi Ide, Ryo Nakamura, Ken ichi Arimura, Kensuke Egashira, Akira Takeshita, Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes, Cardiovascular research, 10.1016/S0008-6363(99)00058-9, 43, 1, 157-164, 1999.01, Objective: The acute administration of growth hormone (GH) or insulin- like growth factor-1 (IGF-1) improves cardiac performance, possibly contributing to the beneficial effects of GH therapy on heart failure (HF). GH can induce the production of IGF-1 and thus the actions of GH may be mediated through its IGF-1 induction. However, these effects have not yet been demonstrated in failing hearts and the cellular basis of GH or IGF-1- induced inotropic effects remains unknown. We examined the direct effects of GH and IGF-1 on the contractile function and intracellular calcium ([Ca2+](i)) homeostasis in normal and failing myocytes. Methods: To determine whether GH and IGF-1 have a direct effect on myocardial contractility and whether the GH/IGF-1-induced effect was the results of changes in Ca2+ activation, cell shortening and [Ca2+](i) transient were simultaneously measured in the left ventricular myocyte preparations, isolated from normal and rapid pacing-induced HF dogs. Results: Basal shortening of HF myocytes was reduced by 64% (p<0.01). In normal and HF myocytes, GH (0.4-40 x 10-3 IU/ml) had no effect on either cell shortening or [Ca2+](i) transients. In normal myocytes, IGF-1 exerted a positive inotropic effect in a time- and dose-dependent manner (25-500 ng/ml), associated with a parallel increase of [Ca2+](i) transient amplitude. IGF- 1 increased the shortening magnitude in normal (121±5% increase from baseline, p<0.05) and HF (118±4% increase from baseline, p<0.05) myocytes. It also increased [Ca2+](i) transient amplitude in normal and HF cells by 124±4 and 125±7%, respectively. The percent increase of cell shortening and [Ca2+](i) transient amplitude was comparable between normal and HF myocytes. Furthermore, IGF-1 did not shift the trajectory of the relaxation phase in the phase-plane plots of cell length vs. [Ca2+](i), indicating that it did not change myofilament Ca2+ sensitivity. Conclusions: In both normal and HF conditions, IGF-1 exerted an acute direct positive inotropic effect in adult cardiac myocytes by increasing the availability of [Ca2+](i) to the myofilaments, possibly explaining the beneficial effect of GH on HF..
136. Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, Utsumi H, Hamasaki N, Takeshita A., Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction., 88(5):529-35..