Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Shoji Matsushima Last modified date:2021.07.12

Assistant Professor / Research Institute of Angiocardiology / Faculty of Medical Sciences


Papers
1. Masaki Ikeuchi, Hiroyuki Tsutsui, Tetsuya Shiomi, Hidenori Matsusaka, Shouji Matsushima, Jing Wen, Toru Kubota, Akira Takeshita, Inhibition of TGF-β signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction, Cardiovascular research, 10.1016/j.cardiores.2004.07.017, 64, 3, 526-535, 2004.12, Transforming growth factor (TGF)-β promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts. Anterior MI was produced in mice by ligating the left coronary artery. TGF-β mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-β signaling during the early phase of MI, an extracellular domain of TGF-β type II receptor (TβIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation. TβIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-α, interleukin-1β, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-β signaling during the later phase, TβIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TβIIR. The activation of TGF-β is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI..
2. Masaki Ikeuchi, Hidenori Matsusaka, Dongchon Kang, Shouji Matsushima, Tomomi Ide, Toru Kubota, Toshiyuki Fujiwara, Naotaka Hamasaki, Akira Takeshita, Kenji Sunagawa, Hiroyuki Tsutsui, 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, 2005.08, Background - Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state. Methods and Results - We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type (WT) littermates (WT-MI), although infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in Tg-MI. LV end-diastolic pressure was increased in WT-MI, and it was also reduced in Tg-MI. Improvement of LV function in Tg-MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis as well as oxidative stress in the noninfarcted LV. Conclusions - Overexpression of TFAM inhibited LV remodeling after MI. TFAM may provide a novel therapeutic strategy of cardiac failure..
3. Hidenori Matsusaka, Masaki Ikeuchi, Shouji Matsushima, Tomomi Ide, Toru Kubota, Arthur M. Feldman, Akira Takeshita, Kenji Sunagawa, Hiroyuki Tsutsui, Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00216.2005, 289, 5 58-5, H1858-H1864, 2005.11, Tumor necrosis factor-α (TNF-α) plays a pathophysiological role in the development and progression of heart failure. Matrix metalloproteinase (MMP)-2 is involved in extracellular matrix remodeling. Recent evidence suggests a protective role for this protease against tissue inflammation. Although MMP-2 is upregulated in the failing heart, little is known about its pathophysiological role. We thus hypothesized that ablation of the MMP-2 gene could affect cardiac remodeling and failure in TNF-α-induced cardiomyopathy. We crossed transgenic mice with cardiac-specific overexpression of TNF-α (TG) with MMP-2 knockout (KO) mice. Four groups of male and female mice were studied: wild-type (WT) with wild MMP-2 (WT/MMP+/+), WT with MMP-2 KO (WT/MMP-/-), TNF-α TG with wild MMP-2 (TG/MMP+/+), and TG with MMP-2 KO (TG/MMP-/-). The upregulation of MMP-2 zymographic activity in TG/MMP+/+ mice was completely abolished in TG/MMP-/- mice, and other MMPs and tissue inhibitors of metalloproteinase were comparable between groups. Survival was shorter for male TG/ MMP-/- than TG/MMP+/+ mice. Female TG/MMP-/- mice were more severely affected than TG/MMP+/+ mice with diminished cardiac function. Myocardial TNF-α and other proinflammatory cytokines were increased in TG/MMP+/+ mice, and this increase was similarly observed in TG/MMP-/- mice. The extent of myocardial infiltrating cells including macrophages was greater in TG/MMP -/- than in TG/MMP+/+ mice. Selective ablation of the MMP-2 gene reduces survival and exacerbates cardiac failure in association with the increased level of myocardial inflammation. MMP-2 may play a cardioprotective role in the pathogenesis of cytokine-induced cardiomyopathy..
4. Shouji 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, H2237-H2245, 2006, 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..
5. Hidenori Matsusaka, Tomomi Ide, Shouji 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..
6. Shouji 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..
7. Hidenori Matsusaka, Tomomi Ide, Shouji 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..
8. Hidenori Matsusaka, Shintaro Kinugawa, Tomomi Ide, Shouji 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..
9. Hiroyuki Tsutsui, Shouji 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..
10. Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Oxidative stress and mitochondrial DNA damage in heart failure, Circulation Journal, 10.1253/circj.CJ-08-0014, 72, SUPPL. A, A31-A37, 2008, 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 while antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage in the failing myocardium. 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, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of peroxiredoxin-3 (Prx-3), mitochon-drial antioxidant, or mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities is also prevented. Therefore, the activation of Prx-3 or TFAM expression could ameliorate the pathophysiological processes seen in myocardial failure. Inhibition of oxidative stress and mtDNA damage could be novel and potentially effective treatment strategies for heart failure..
11. Hiroshi Asajima, Yohei Sekiguchi, Shoji Matsushima, Naotaka Saito, Takahiko Saito, QT prolongation and torsade de pointes associated with solifenacin in an 81-year-old woman, British journal of clinical pharmacology, 10.1111/j.1365-2125.2008.03298.x, 66, 6, 896-897, 2008.12.
12. Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Mitochondrial oxidative stress and dysfunction in myocardial remodelling, Cardiovascular research, 10.1093/cvr/cvn280, 81, 3, 449-456, 2009.02, Recent experimental and clinical studies have suggested that oxidative stress is enhanced in myocardial remodelling and failure. The production of oxygen radicals is increased in the failing heart, whereas normal antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and can be a therapeutic target against oxidant-induced damage in the failing myocardium. 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 myocardial remodelling and failure. Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of the genes for peroxiredoxin-3 (Prx-3), a mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM), could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in mitochondrial function was also prevented. Therefore, the activation of Prx-3 or TFAM gene expression could ameliorate the pathophysiological processes seen in mitochondrial dysfunction and myocardial remodelling. Inhibition of oxidative stress and mtDNA damage could be novel and effective treatment strategies for heart failure..
13. Takahiko Saito, Masatoshi Motohashi, Shouji Matsushima, Naotaka Saito, Takehiro Kubota, Kimitaka Tasai, Hiroshi Asajima, Left main coronary artery atresia diagnosed by multidetector computed tomography, International Journal of Cardiology, 10.1016/j.ijcard.2008.03.068, 135, 1, e27-e29, 2009.06, Left main coronary artery atresia is an extremely rare disease. Differential diagnosis of left main coronary artery atresia from atherosclerotic occlusion of left main coronary artery is difficult even if performing invasive coronary angiography. We present a case of a 48-year-old male with left main coronary artery atresia. Echocardiography showed left ventricular dysfunction. Invasive coronary angiography showed absence of left main coronary artery. A multidetector computed tomography showed a string-like structure at the site of left main coronary artery. A diagnosis of left main coronary artery atresia was made, and he underwent coronary artery bypass grafting. At the operation, a thin and not-sclerotic left main coronary artery was observed. Echocardiography, performed after the surgery, showed normalization of the left ventricular systolic function. Multidetector computed tomography might be a useful method to diagnose left main coronary artery atresia..
14. Shouji Matsushima, Shintaro Kinugawa, Takashi Yokota, Naoki Inoue, Yukihiro Ohta, Sanae Hamaguchi, Hiroyuki Tsutsui, Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.01332.2008, 297, 1, H409-H416, 2009.07, Type 2 diabetes adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) failure. NAD(P)H oxidase-derived superoxide (O2-) production is increased in type 2 diabetes. However, its pathophysiological significance in advanced post-MI LV failure associated with type 2 diabetes remains unestablished. We thus hypothesized that an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV failure after MI in high-fat diet (HFD)-induced obese mice with type 2 diabetes. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 wk. At 4 wk of feeding, MI was created in mice by ligating the left coronary artery. HFD-fed MI mice were treated with either 10 mmol/l apocynin or vehicle. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 ± 0.1 vs. 5.3 ± 0.2 mm), end-diastolic pressure (12 ± 2 vs. 8 ± 1 mmHg), and lung weight/tibial length (10.1 ± 0.3 vs. 8.7 ± 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD + MI with apocynin significantly decreased LVEDD (5.4 ± 0.1 mm), LV end-diastolic pressure (9.7 ± 0.8 mmHg), lung weight/tibial length (9.0 ± 0.3 mg/mm), and concomitantly interstitial fibrosis of noninfarcted LV to the ND + MI level without affecting body weight, glucose metabolism, and infarct size. NAD(P)H oxidase activity and O 2- production were increased in noninfarcted LV tissues from HFD + MI, both of which were attenuated by apocynin to the ND + MI level. Type 2 diabetes was associated with the exacerbation of LV failure after MI via increasing NAD(P)H oxidase-derived O2-, which may be a novel important therapeutic target in advanced heart failure with diabetes..
15. Takashi Yokota, Shintaro Kinugawa, Kagami Hirabayashi, Shouji Matsushima, Naoki Inoue, Yukihiro Ohta, Sanae Hamaguchi, Mochamad A. Sobirin, Taisuke Ono, Tadashi Suga, Satoshi Kuroda, Shinya Tanaka, Fumio Terasaki, Koichi Okita, Hiroyuki Tsutsui, Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00267.2009, 297, 3, H1069-H1077, 2009.09, Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (V̇O 2). The work (vertical distance X body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak V̇O 2. Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes..
16. Junya Kuroda, Tetsuro Ago, Shouji Matsushima, Peiyong Zhai, Michael D. Schneider, Junichi Sadoshima, NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1002178107, 107, 35, 15565-15570, 2010.08, NAD(P)H oxidases (Noxs) produce O2- and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4-/- (c-Nox4-/-) mice. Nox4 expression was inhibited in c-Nox4 -/- mice in a heart-specific manner, and there was no compensatory up-regulationin other Nox enzymes. These mice exhibited reducedlevels of O 2- in the heart, indicating that Nox4 is a significant source of O2- in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4-/- mice. In response to pressure overload (PO), however, increases in Nox4 expression and O2 - production in mitochondria were abolished in c-Nox4-/- mice, and c-Nox4-/- mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4-/- mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO..
17. Mamoru Sakakibara, Shiro Yamada, Shouji Matsushima, Akimichi Saito, Yoshihiro Masaki, Tsuneaki Honma, Suguru Kubota, Yoshiro Matsui, Hiroyuki Tsutsui, Successful adaptive servo-ventilation for patients with acute cardiogenic pulmonary edema due to severe aortic stenosis, Journal of Cardiology Cases, 10.1016/j.jccase.2010.05.003, 2, 2, e115-e118, 2010.10, A 60-year-old woman with severe aortic stenosis (AS) and congenital bicuspid aortic valve was admitted to our hospital due to cardiogenic pulmonary edema. Noninvasive adaptive servo-ventilation (ASV) improved her symptoms and respiratory status. It was associated with favorable hemodynamic effects including an increase in cardiac output and a decrease in pulmonary vascular resistance without alternating systemic blood pressure. An improvement in oxygenation and the favorable hemodynamic effects might lead to the stabilization of clinical status. Noninvasive ventilation with ASV can avert tracheal intubation by improving oxygenation and is expected to be convenient and useful in the treatment of acute pulmonary edema..
18. Chiao Po Hsu, Peiyong Zhai, Takanobu Yamamoto, Yasuhiro Maejima, Shouji Matsushima, Nirmala Hariharan, Dan Shao, Hiromitsu Takagi, Shinichi Oka, Junichi Sadoshima, Silent information regulator 1 protects the heart from ischemia/reperfusion, Circulation, 10.1161/CIRCULATIONAHA.110.958033, 122, 21, 2170-2182, 2010.11, Background-: Silent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R). Methods and results-: Protein and mRNA expression of Sirt1 is significantly reduced by I/R. Cardiac-specific Sirt1 mice exhibited a significant increase (44±5% versus 15±5%; P=0.01) in the size of myocardial infarction/area at risk. In transgenic mice with cardiac-specific overexpression of Sirt1, both myocardial infarction/area at risk (15±4% versus 36±8%; P=0.004) and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei (4±3% versus 10±1%; P<0.003) were significantly reduced compared with nontransgenic mice. In Langendorff-perfused hearts, the functional recovery during reperfusion was significantly greater in transgenic mice with cardiac-specific overexpression of Sirt1 than in nontransgenic mice. Sirt1 positively regulates expression of prosurvival molecules, including manganese superoxide dismutase, thioredoxin-1, and Bcl-xL, whereas it negatively regulates the proapoptotic molecules Bax and cleaved caspase-3. The level of oxidative stress after I/R, as evaluated by anti-8-hydroxydeoxyguanosine staining, was negatively regulated by Sirt1. Sirt1 stimulates the transcriptional activity of FoxO1, which in turn plays an essential role in mediating Sirt1-induced upregulation of manganese superoxide dismutase and suppression of oxidative stress in cardiac myocytes. Sirt1 plays an important role in mediating I/R-induced increases in the nuclear localization of FoxO1 in vivo. Conclusions-: These results suggest that Sirt1 protects the heart from I/R injury through upregulation of antioxidants and downregulation of proapoptotic molecules through activation of FoxO and decreases in oxidative stress..
19. Tetsuro Ago, Shouji Matsushima, Junya Kuroda, Daniela Zablocki, Takanari Kitazono, Junichi Sadoshima, The NADPH oxidase Nox4 and aging in the heart, Aging, 10.18632/aging.100261, 2, 12, 1012-1016, 2010.12, Oxidative stress in mitochondria is believed to promote aging. Although passive leakage of electron from the m itochondrial electron transport chain has been considered as a major source of oxidative stress in the heart and the cardiomyocytes therein, enzymes actively producing reactive oxygen species may also exist in mitochondria. We have shown recently that Nox4, a member of the NADPH oxidase family, is localized on intracellular membranes, primarily at mitochondria, in cardiomyocytes. Mitochondrial expression of Nox4 is upregulated by cardiac stress and aging in the heart, where Nox4 could become a major source of oxidative stress. This raises an intriguing possibility that Nox4 may play an important role in mediating aging of the heart. Here we discuss the potential involvement of Nox4 in mitochondrial oxidative stress and aging in the heart..
20. Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Takashi Yokota, Oxidative stress in cardiac and skeletal muscle dysfunction associated with diabetes mellitus, Journal of Clinical Biochemistry and Nutrition, 10.3164/jcbn.11-012FR, 48, 1, 68-71, 2011.01, Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease. It also causes skeletal muscle dysfunction, which is responsible for reduced exercise capacity commonly seen in heart failure. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac and skeletal muscle dysfunction in heart failure and diabetes mellitus. Based on the findings in animal models, this review discusses the role of oxidative stress that may be involved in the development and progression of cardiac and skeletal dysfunction associated with diabetes..
21. Yasuhiro Maejima, Junya Kuroda, Shouji Matsushima, Tetsuro Ago, Junichi Sadoshima, Regulation of myocardial growth and death by NADPH oxidase, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2010.12.018, 50, 3, 408-416, 2011.03, The NADPH oxidases (Nox) are transmembrane proteins dedicated to producing reactive oxygen species (ROS), including superoxide and hydrogen peroxide, by transferring electrons from NAD(P)H to molecular oxygen. Nox2 and Nox4 are expressed in the heart and play an important role in mediating oxidative stress at baseline and under stress. Nox2 is primarily localized on the plasma membrane, whereas Nox4 is found primarily on intracellular membranes, on mitochondria, the endoplasmic reticulum or the nucleus. Although Nox2 plays an important role in mediating angiotensin II-induced cardiac hypertrophy, Nox4 mediates cardiac hypertrophy and heart failure in response to pressure overload. Expression of Nox4 is upregulated by hypertrophic stimuli, and Nox4 in mitochondria plays an essential role in mediating oxidative stress during pressure overload-induced cardiac hypertrophy. Upregulation of Nox4 induces oxidation of mitochondrial proteins, including aconitase, thereby causing mitochondrial dysfunction and myocardial cell death. On the other hand, Noxs also appear to mediate physiological functions, such as erythropoiesis and angiogenesis. In this review, we discuss the role of Noxs in mediating oxidative stress and both pathological and physiological functions of Noxs in the heart..
22. Shiro Yamada, Mamoru Sakakibara, Shouji Matsushima, Akimichi Saito, Tsuneaki Homma, Arata Fukushima, Yoshihiro Masaki, Masaya Watanabe, Hirofumi Mitsuyama, Hisashi Yokoshiki, Hiroyuki Tsutsui, Successful termination of recurrent ventricular arrhythmias by adaptive servo-ventilation in a patient with heart failure, Journal of Cardiology Cases, 10.1016/j.jccase.2011.01.001, 3, 2, e57-e61, 2011.04, A 60-year-old woman who underwent operation due to severe aortic stenosis with left ventricular dysfunction had frequent nonsustained ventricular tachycardia (NSVT) at night. She had an increased apnea-hypopnea index and a reduction in minimum O2 saturation during sleep, which was closely associated with the frequency of NSVT. Adaptive servo-ventilation (ASV) therapy improved sleep disorder breathing (SDB) and also reduced ventricular arrhythmias. These effects were associated with the attenuation of the sympathetic nerve activities by the analysis of heart rate variability. ASV is expected to be effective in the treatment of ventricular tachyarrhythmias in patients with heart failure and SDB..
23. Yukihiro Ohta, Shintaro Kinugawa, Shouji Matsushima, Taisuke Ono, Mochamad A. Sobirin, Naoki Inoue, Takashi Yokota, Kagami Hirabayashi, Hiroyuki Tsutsui, Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.01185.2009, 300, 5, H1637-H1644, 2011.05, Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) (30). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase..
24. Shouji Matsushima, Daniela Zablocki, Junichi Sadoshima, Application of recombinant thioredoxin1 for treatment of heart disease, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2010.09.020, 51, 4, 570-573, 2011.10, Thioredoxin 1 (Trx1) is a small molecule with reactive cysteines that reduces proteins with disulfide bonds through a thiol disulfide exchange reaction. Accumulating lines of evidence suggest that Trx1 protects the heart from ischemia/reperfusion injury, pathological hypertrophy, and inflammation; induces preconditioning effects and angiogenesis; and upregulates mitochondrial genes. Exogenously given recombinant Trx1 (r-Trx1) may protect the heart through its actions in both extracellular and intracellular spaces. In this brief review, the potential of Trx1 therapy for heart disease is discussed. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."..
25. Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Oxidative stress and heart failure, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00554.2011, 301, 6, 2181-2190, 2011.12, Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, has been shown to play an important role in the pathophysiology of cardiac remodeling and heart failure (HF). It induces subtle changes in intracellular pathways, redox signaling, at lower levels, but causes cellular dysfunction and damage at higher levels. ROS are derived from several intracellular sources, including mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. The production of ROS is increased within the mitochondria from failing hearts, whereas normal antioxidant enzyme activities are preserved. Chronic increases in ROS production in the mitochondria lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further ROS generation, and cellular injury. ROS directly impair contractile function by modifying proteins central to excitation-contraction coupling. Moreover, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases, leading to the extracellular matrix remodeling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure. Oxidative stress is also involved in the skeletal muscle dysfunction, which may be associated with exercise intolerance and insulin resistance in HF. Therefore, oxidative stress is involved in the pathophysiology of HF in the heart as well as in the skeletal muscle. A better understanding of these mechanisms may enable the development of novel and effective therapeutic strategies against HF..
26. Shouji Matsushima, Junya Kuroda, Tetsuro Ago, Peiyong Zhai, Ji Yeon Park, Lai Hua Xie, Bin Tian, Junichi Sadoshima, Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy, Circulation research, 10.1161/CIRCRESAHA.112.279760, 112, 4, 651-663, 2013.02, Rationale: Oxidation of cysteine residues in class II histone deacetylases (HDACs), including HDAC4, causes nuclear exit, thereby inducing cardiac hypertrophy. The cellular source of reactive oxygen species responsible for oxidation of HDAC4 remains unknown. Objective: We investigated whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), a major nicotinamide adenine dinucleotide phosphate oxidase, mediates cysteine oxidation of HDAC4. Methods and Results: Phenylephrine (100 μmol/L), an α1 adrenergic agonist, induced upregulation of Nox4 (1.5-fold; P<0.05) within 5 minutes, accompanied by increases in O2 (3.5-fold; P<0.01) from the nuclear membrane and nuclear exit of HDAC4 in cardiomyocytes. Knockdown of Nox4, but not Nox2, attenuated O2 production in the nucleus and prevented phenylephrine-induced oxidation and nuclear exit of HDAC4. After continuous infusion of phenylephrine (20 mg/kg per day) for 14 days, wild-type and cardiac-specific Nox4 knockout mice exhibited similar aortic pressures. Left ventricular weight/tibial length (5.7±0.2 versus 6.4±0.2 mg/mm; P<0.05) and cardiomyocytes cross-sectional area (223±13 versus 258±12 μm; P<0.05) were significantly smaller in cardiac-specific Nox4 knockout than in wild-type mice. Nuclear O2production in the heart was significantly lower in cardiac-specific Nox4 knockout than in wild-type mice (4116±314 versus 7057±1710 relative light unit; P<0.05), and cysteine oxidation of HDAC4 was decreased. HDAC4 oxidation and cardiac hypertrophy were also attenuated in cardiac-specific Nox4 knockout mice 2 weeks after transverse aortic constriction. Conclusions: Nox4 plays an essential role in mediating cysteine oxidation and nuclear exit of HDAC4, thereby mediating cardiac hypertrophy in response to phenylephrine and pressure overload..
27. Tim Christian Zschauer, Shouji Matsushima, Joachim Altschmied, Dan Shao, Junichi Sadoshima, Judith Haendeler, Interacting with thioredoxin-1-disease or no disease?, Antioxidants and Redox Signaling, 10.1089/ars.2012.4822, 18, 9, 1053-1062, 2013.03, Significance: Many cardiovascular disorders are accompanied by a deregulated cellular redox balance resulting in elevated levels of intracellular reactive oxygen species (ROS). One major antioxidative cellular molecule is thioredoxin-1 (Trx-1). Its indispensability is demonstrated by the embryonic lethality of Trx-1 deficient mice. Trx-1 is ubiquitously expressed in cells and has numerous, diverse functions. It not only reduces oxidized proteins or, together with peroxiredoxins, detoxifies H2O2, but also binds to several proteins and thereby regulates their functions. The interaction partners of Trx-1 differ depending on its localization in the cytosol or in the nucleus. Recent Advances/Critical Issues: Over the past decade it has become clear that Trx-1 is not only critical for tumor functions, which has resulted in therapeutic approaches targeting this protein, but also essential for proper functions of the vasculature and the heart. Changes in post-translational modifications of Trx-1 or in its interactions with other proteins can lead to a switch from a physiologic state of cells and organs to diverse pathologies. This review provides insights into the role of Trx-1 in different physiological situations and cardiac hypertrophy, ischemia reperfusion injury, heart failure, atherosclerosis, and diabetes mellitus type 2, underscoring the central role of Trx-1 in cardiovascular health and disease. Future Directions: Thus, the manipulation of Trx-1 activity in the heart and/or vasculature, for example, by small molecules, seems to be a promising therapeutic option in cardiovascular diseases, as general anti-oxidant treatments would not take into account interactions of Trx-1 with other proteins and also eliminate vital ROS..
28. Shouji Matsushima, Junya Kuroda, Tetsuro Ago, Peiyong Zhai, Yoshiyuki Ikeda, Shinichi Oka, Guo Hua Fong, Rong Tian, Junichi Sadoshima, Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α, Circulation research, 10.1161/CIRCRESAHA.111.300171, 112, 8, 1135-1149, 2013.04, RATIONALE: NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O 2- and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. OBJECTIVE: We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. METHODS AND RESULTS: Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2- production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2- production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator-activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator-activated receptor-α in Tg-dominant-negative Nox mice. A cross with peroxisome proliferator-activated receptor-α KO mice also attenuated the injury in Tg- dominant-negative Nox mice. CONCLUSIONS: Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator-activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation..
29. Atsuro Masuda, Osamu Manabe, Masanao Naya, Noriko Oyama-Manabe, Shiro Yamada, Shouji Matsushima, Florian Gaertner, Satoshi Yamada, Hiroyuki Tsutsui, Nagara Tamaki, Whole body assessment by 18 F-FDG PET in a patient with infective endocarditis, Journal of Nuclear Cardiology, 10.1007/s12350-013-9722-2, 20, 4, 641-643, 2013.08.
30. Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takahiro Abe, Tadashi Suga, Shingo Takada, Tomoyasu Kadoguchi, Koichi Okita, Shouji Matsushima, Hiroyuki Tsutsui, Increased plasma soluble (pro)renin receptor levels are correlated with renal dysfunction in patients with heart failure, International Journal of Cardiology, 10.1016/j.ijcard.2013.04.176, 168, 4, 4313-4314, 2013.10.
31. Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takashi Yokota, Shouji Matsushima, Takahiro Abe, Tadashi Suga, Shingo Takada, Tomoyasu Kadoguchi, Ryoichi Katsuyama, Koji Oba, Koichi Okita, Hiroyuki Tsutsui, Decreased serum brain-derived neurotrophic factor levels are correlated with exercise intolerance in patients with heart failure, International Journal of Cardiology, 10.1016/j.ijcard.2013.08.073, 168, 5, e142-e144, 2013.10.
32. Qiujun Yu, Chi Fung Lee, Wang Wang, Georgios Karamanlidis, Junya Kuroda, Shouji Matsushima, Junichi Sadoshima, Rong Tian, Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury., Journal of the American Heart Association, 10.1161/JAHA.113.000555, 3, 1, e000555, 2014, The NADPH oxidase family (Nox) produces reactive oxygen species by adding the electron donated by NADPH to oxygen. Excessive reactive oxygen species production under a variety of pathological conditions has been attributed to increased Nox activity. Here, we aimed at investigating the role of Nox in cardiac ischemic injury through gain- and loss-of-function approaches. We modulated Nox activity in the heart by cardiac-specific expression of Nox4 and dominant negative Nox4. Modulation of Nox activity drastically changes the cellular redox status. Increasing Nox activity by cardiac-specific overexpression of Nox4 imposed oxidative stress on the myocardium [increased NAD(P)(+)/NAD(P)H and decreased glutathione/glutathione disulfide ratio] and worsened cardiac energetics and contractile function after ischemia-reperfusion. Overexpression of the dominant negative Nox4 (DN), which abolished the Nox function, led to a markedly reduced state [decreased NAD(P)(+)/NAD(P)H and increased glutathione/glutathione disulfide ratio] at baseline and paradoxically promoted mitochondrial reactive oxygen species production during ischemia resulting in no recovery of heart function after reperfusion. Limiting the generation of reducing equivalent through modulating carbon substrates availability partially restored the NAD(+)/NADH ratio and protected dominant negative Nox4 hearts from ischemic injury. This study reveals an important role of Nox in cardiac redox regulation and highlights the complexity of developing therapies that affect the intricately connected redox states..
33. Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Shouji Matsushima, Mamoru Sakakibara, Naoki Ishimori, Daisuke Goto, Hiroyuki Tsutsui, Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure, Journal of Cardiology, 10.1016/j.jjcc.2013.07.012, 63, 3, 182-188, 2014.03, Background and purpose: Hyponatremia is common and is associated with poor in-hospital outcomes in patients hospitalized with heart failure (HF). However, it is unknown whether hyponatremia is associated with long-term adverse outcomes. The purpose of this study was to clarify the characteristics, clinical status on admission, and management during hospitalization according to the serum sodium concentration on admission, and determine whether hyponatremia was associated with in-hospital as well as long-term outcomes in 1677 patients hospitalized with worsening HF on index hospitalization registered in the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Methods and subjects: We studied the characteristics and in-hospital treatment in 1659 patients hospitalized with worsening HF by using the JCARE-CARD database. Patients were divided into 2 groups according to serum sodium concentration on admission <135. mEq/mL (n= 176; 10.6%) or ≥135. mEq/mL (n= 1483; 89.4%). Results: The mean age was 70.7 years and 59.2% were male. Etiology was ischemic in 33.9% and mean left ventricular ejection fraction was 42.4%. After adjustment for covariates, hyponatremia was independently associated with in-hospital death [adjusted odds ratio (OR) 2.453, 95% confidence interval (CI) 1.265-4.755, p= 0.008]. It was significantly associated also with adverse long-term (mean 2.1. ±. 0.8 years) outcomes including all-cause death (OR 1.952, 95% CI 1.433-2.657), cardiac death (OR 2.053, 95% CI 1.413-2.983), and rehospitalization due to worsening HF (OR 1.488, 95% CI 1.134-1.953). Conclusions: Hyponatremia was independently associated with not only in-hospital but also long-term adverse outcomes in patients hospitalized with worsening HF..
34. Shouji Matsushima, Hiroyuki Tsutsui, Junichi Sadoshima, Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion, Trends in Cardiovascular Medicine, 10.1016/j.tcm.2014.03.003, 24, 5, 202-205, 2014.07, Oxidative stress, the presence of reactive oxygen species (ROS) in excess of the antioxidant capacity in the heart induces myocardial damage, accumulation of which leads to ischemic heart disease and heart failure. NADPH oxidase (Nox) 2 and 4 are the major sources of O2- and H2O2 in the heart and play a crucial role in the regulation of growth and death in cardiomyocytes. Both Nox2 and Nox4 are upregulated in response to ischemia-reperfusion (I/R), thereby contributing to ROS production and consequent myocardial injury. Suppression of either one of them can reduce ROS and I/R injury in the heart. Importantly, however, a minimum level of ROS production by either Nox2 or Nox4 is essential for the activation of HIF-1α and inhibition of PPARα during I/R, such that combined suppression of both Nox2 and Nox4 exacerbates myocardial I/R injury. Thus, either excessive activation or suppression of Noxs below physiological levels can induce cardiac injury. Here we discuss both detrimental and salutary functions of Nox isoforms during myocardial I/R..
35. Sanae Hamaguchi, Shintaro Kinugawa, Shouji Matsushima, Arata Fukushima, Takashi Yokota, Mamoru Sakakibara, Hisashi Yokoshiki, Miyuki Tsuchihashi-Makaya, Hiroyuki Tsutsui, Clinical characteristics and CHADS2 score in patients with heart failure and atrial fibrillation
Insights from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), International Journal of Cardiology, 10.1016/j.ijcard.2014.06.068, 176, 1, 239-242, 2014.09.
36. Arata Fukushima, Shintaro Kinugawa, Shingo Takada, Shouji Matsushima, Mochamad Ali Sobirin, Taisuke Ono, Masashige Takahashi, Tadashi Suga, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Tomoyasu Kadoguchi, Takashi Yokota, Koichi Okita, Hiroyuki Tsutsui, (Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice, American Journal of Physiology - Endocrinology and Metabolism, 10.1152/ajpendo.00449.2013, 307, 6, E503-E514, 2014.09, We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg-1·day-1, n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF..
37. Shingo Takada, Kagami Hirabayashi, Shintaro Kinugawa, Takashi Yokota, Shouji Matsushima, Tadashi Suga, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Wataru Mizushima, Yoshihiro Masaki, Takaaki Furihata, Ryoichi Katsuyama, Koichi Okita, Hiroyuki Tsutsui, Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice, European Journal of Pharmacology, 10.1016/j.ejphar.2014.06.008, 740, 690-696, 2014.10, We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin-sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3 mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, HFD+vehicle, and HFD+pioglitazone (n=10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND+vehicle group. Pioglitazone normalized the insulin levels in HFD-fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP-dependent mitochondrial respiration, complex I and III activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondrial function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus..
38. Kagami Hirabayashi, Shintaro Kinugawa, Takashi Yokota, Shingo Takada, Arata Fukushima, Tadashi Suga, Masashige Takahashi, Taisuke Ono, Noriteru Morita, Masashi Omokawa, Kuniaki Harada, Noriko Oyama-Manabe, Hiroaki Shirato, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Intramyocellular lipid is increased in the skeletal muscle of patients with dilated cardiomyopathy with lowered exercise capacity, International Journal of Cardiology, 10.1016/j.ijcard.2014.07.113, 176, 3, 1110-1112, 2014.10.
39. Toshio Ogihara, Takao Saruta, Hiromi Rakugi, Ikuo Saito, Kazuaki Shimamoto, Hiroaki Matsuoka, Kazuyuki Shimada, Sadayoshi Ito, Masatsugu Horiuchi, Tsutomu Imaizumi, Shuichi Takishita, Jitsuo Higaki, Shigehiro Katayama, Genjiroh Kimura, Satoshi Umemura, Nobuyuki Ura, Koichi Hayashi, Masato Odawara, Norio Tanahashi, Toshihiko Ishimitsu, Naoki Kashihara, Satoshi Morita, Satoshi Teramukai, T. Anno, S. Aoyama, N. Arima, Y. Bando, Y. Dohi, H. Fujioka, M. Fukuda, S. Fukuda, M. Fukuta, Y. Futamura, Y. Hirakawa, K. Imaeda, H. Imai, A. Imamura, M. Ito, O. Ito, T. Ito, T. Iwa, J. Izumi, Y. Kaga, K. Kanematsu, Y. Kato, Y. Kawata, T. Kitamura, K. Kobayashi, M. Koyasu, S. Kuwabara, M. Kuzuya, M. Maekawa, H. Mihara, F. Mitsuguchi, T. Murohara, T. Narita, K. Negi, Y. Numaguchi, T. Ohya, N. Okayama, K. Okuma, N. Ozaki, N. Ozeki, K. Sato, T. Sawada, Y. Seino, M. Suezawa, T. Suzuki, Y. Suzuki, N. Takahashi, R. Takahashi, N. Tanaka, Y. Wakida, H. Watanuki, M. Watarai, K. Yamada, S. Yamashita, M. Yoshikane, M. Goto, Y. Ishida, H. Kimura, K. Takahashi, N. Yashima, Y. Abe, S. Fujiwara, H. Higashino, M. Kaizuka, O. Minami, Y. Ogiu, T. Osanai, T. Sasaki, A. Sato, K. Sugimoto, H. Takahashi, K. Tanabe, D. Azuma, C. Ibuki, H. Inoya, T. Iyo, M. Kusaka, M. Ogawa, Y. Okubo, H. Rinno, M. Sano, T. Shishikura, H. Takahara, M. Takano, T. Takemura, S. Yamamoto, Y. Yonemitsu, M. Hasui, T. Honda, M. Igase, S. Kimoto, K. Kohno, S. Kondo, T. Oonishi, H. Saeki, T. Sunayama, H. Takahashi, C. Wakisaka, H. Watanabe, K. Watanabe, Y. Iwahori, Alan H.C. Lau, S. Ando, H. Eguchi, M. Fujino, J. Fukui, T. Gondo, S. Hatakeyama, K. Hirano, Y. Hirooka, H. Ikeda, T. Inou, T. Jinnouchi, T. Kadokami, H. Kai, H. Kameo, M. Kaneyuki, A. Katoh, H. Kishikawa, H. Koiwaya, K. Kusaba, S. Maeda, S. Maki, M. Matsumoto, T. Matsumoto, J. Matsumura, S. Matsuo, H. Meno, S. Miki, J. Miyagi, T. Miyauchi, S. Mori, M. Nagashima, S. Nagata, R. Nakamura, T. Nakamura, H. Niiyama, K. Noda, M. Nohara, Y. Ohta, I. Onitsuka, T. Otonari, S. Ouma, T. Sakisaka, K. Saku, K. Sasaki, S. Sasaki, Y. Sawayama, M. Shihara, K. Shiota, K. Shirakawa, Y. Tachikawa, S. Takemura, T. Takeuchi, M. Tanabe, M. Tanaka, H. Tashiro, M. Tatsukawa, T. Tsuchihashi, T. Tsuiki, T. Tsutsui, Y. Uehara, H. Umei, T. Yamada, J. Yamagata, T. Ajihara, K. Hagiwara, S. Imamura, M. Inoue, I. Konno, K. Konta, Y. Kubota, H. Kumakawa, T. Kuwana, H. Mitsuhashi, Y. Miyazaki, J. Nagashima, M. Nambu, T. Nishimaki, M. Sato, Y. Taneda, T. Tezuka, T. Yabuki, F. Ando, Y. Fuwa, S. Umeda, O. Araki, Y. Furushima, Y. Hattori, H. Hirabayashi, M. Horigome, J. Hoshino, C. Iguchi, H. Inamura, H. Kawauchi, S. Kogure, H. Kubo, F. Naganuma, T. Nagao, T. Nagao, T. Nagata, H. Nakashima, Y. Shimizu, H. Shoda, M. Tachibana, K. Yabe, R. Kuwashima, R. Mouri, T. Murakami, H. Muraoka, S. Nomura, F. Okuno, N. Sasaki, R. Sasaki, T. Satoh, M. Shirataki, H. Sugino, H. Takahashi, H. Takemoto, J. Ashihara, T. Betsuyaku, T. Fujita, T. Haga, M. Hayashi, Y. Hayashi, K. Hirasawa, Y. Ishii, R. Ishimoto, T. Komakine, M. Kyuma, I. Maeda, H. Matsuda, T. Matsuki, T. Matsumoto, T. Mito, M. Mizutani, H. Morimoto, S. Natori, T. Nishimiya, M. Nishimura, H. Oimatsu, H. Ooiwa, S. Saitoh, Y. Sasagawa, T. Segawa, H. Shuke, K. Sotozono, S. Takagi, S. Tanaka, M. Tashi, T. Tsubokura, Y. Ueno, K. Urabe, K. Yamauchi, H. Yoshida, M. Amano, Y. Hiroumi, K. Iiyama, H. Kido, A. Kosaka, A. Nogami, M. Okada, M. Shigenobu, R. Shigeta, S. Takagi, T. Takamiya, T. Takemura, S. Tomimoto, T. Tsuboi, N. Abe, E. Akaogi, S. Iida, K. Ito, H. Jonouchi, T. Matsushima, H. Miura, M. Miyazaki, S. Okubo, T. Araki, O. Iritani, K. Masuya, S. Morimoto, T. Nakahashi, Y. Wakasa, M. Yanagi, Y. Abe, H. Ito, T. Kawakami, Y. Kawamorita, H. Okamoto, H. Omori, T. Suzuki, T. Yoshida, K. Akiyama, S. Fujita, T. Hamamoto, K. Hasegawa, M. Hattori, H. Imachi, T. Ishida, H. Ishihama, K. Kaifu, H. Kishikawa, M. Kono, M. Kunishige, T. Maeta, H. Masugata, I. Matsumoto, N. Matsuoka, H. Miki, S. Mori, T. Morita, Y. Nishijima, E. Ohashi, Y. Okauchi, T. Okura, Y. Onishi, K. Ono, S. Senda, I. Seo, Y. Sugimoto, M. Tada, K. Yokoi, K. Yoshinare, K. Arikawa, Y. Hayashi, K. Iida, S. Miyata, H. Mizoguchi, A. Osako, S. Saishoji, I. Shimozono, S. Takenouchi, S. Tanaka, T. Furuki, N. Hatori, T. Iwaki, E. Kametsu, T. Kawafune, I. Kobayashi, T. Kubo, I. Michishita, F. Nonaka, H. Numata, A. Ogata, K. Okubo, T. Sano, R. Sawada, T. Sekino, N. Shimizu, H. Shionoiri, H. Tsuchiya, Y. Watanabe, H. Yamamoto, G. Yasuda, M. Aoki, Y. Iwasaki, H. Kawamoto, S. Kitagawa, M. Matsumoto, M. Nishinaga, M. Nishiyama, K. Tsuboi, I. Ueda, T. Yabe, H. Yamada, T. Yoshida, K. Azuma, O. Doi, R. Fukami, Y. Horio, Y. Ichikawa, S. Ikeda, T. Inaba, S. Mimori, K. Ohmori, K. Sasaki, A. Sato, H. Toyama, Y. Toyama, T. Hamasaki, H. Hayashi, T. Isono, S. Kageyama, K. Komaki, S. Matoba, H. Matsubara, T. Matubara, C. Nakagawa, D. Nishi, M. Nishi, K. Oiwa, H. Takamatsu, H. Takashima, T. Takegami, K. Takenaka, H. Yamada, Y. Yasuda, M. Horiguchi, J. Iemura, N. Isaka, T. Ishiga, T. Kato, T. Kitamura, M. Kobayashi, M. Setsuda, K. Shimono, M. Abe, T. Abe, Y. Abe, Y. Akino, H. Ebina, G. Hirasawa, K. Hirasawa, H. Kamada, M. Kishi, K. Kohama, S. Kyogoku, K. Matsuo, Y. Meguro, S. Miyasato, K. Morita, H. Nakagawa, Y. Otake, H. Saito, A. Sasaki, I. Sasaki, S. Sato, N. Uchida, Y. Utsumi, S. Yamaguchi, K. Hosokawa, Y. Ishiyama, S. Kariya, H. Komidori, M. Kuwabara, H. Ohta, S. Sonoda, M. Takii, N. Wake, N. Yokota, A. Iijima, T. Shinozaki, T. Takeda, A. Ito, H. Kawano, Y. Koide, H. Matsuoka, K. Nakao, K. Yamaguchi, A. Yamanaka, Y. Furiya, T. Kimu, Y. Kuga, Y. Nishida, Y. Saito, K. Sugie, T. Takami, M. Yamasaki, Y. Kaneko, H. Kawabata, S. Nakayama, Y. Abe, H. Ando, T. Fujino, K. Gotoh, T. Kakuma, I. Katsuragi, A. Kuroda, T. Masaki, K. Ninomiya, K. Okita, H. Ono, T. Watanabe, A. Yoshiiwa, K. Abe, S. Deguchi, F. Ikeda, H. Kataoka, N. Komai, K. Koten, K. Kusano, N. Maeda, H. Makino, S. Matano, T. Ohe, K. Shikata, M. Gushiken, R. Hamada, K. Matsushima, T. Shimabukuro, S. Tohma, T. Akagi, F. Akai, T. Amatsu, N. Babaya, S. Ban, K. Fujii, M. Fujimoto, Y. Fujimura, S. Fukumoto, M. Funauchi, H. Hanada, K. Hasegawa, N. Hayashi, T. Hibuse, M. Higashida, H. Honde, A. Imagawa, Y. Imamura, S. Inoue, R. Ishii, K. Ishikawa, K. Ishitani, H. Ito, S. Kaito, A. Kamitani, K. Kamiya, N. Kasayuki, R. Kawanami, T. Kawasaki, Y. Kijima, K. Kinoshita, M. Kishibuchi, Y. Kitamura, M. Kobayashi, T. Kono, Y. Maeda, K. Masaki, H. Matsumoto, S. Matsuoka, R. Matsuwaka, K. Minamikata, M. Miyagawa, H. Miyamoto, M. Miyamoto, E. Miyazaki, K. Miyoshi, M. Mune, N. Nakagawa, Y. Nakagawa, F. Nakamura, T. Nakamura, K. Nakanishi, Y. Nakatani, J. Nariyama, H. Nishida, M. Nishino, M. Nishiyama, K. Nishizawa, R. Nohara, A. Nose, H. Ogasawara, R. Ogawa, Y. Ohno, M. Ojima, Y. Okuyama, H. Otani, S. Otani, H. Park, H. Saito, A. Sakai, H. Sakamoto, H. Sata, Y. Sekine, T. Shinozuka, T. Suga, K. Sugimoto, M. Sugiyama, K. Suyama, K. Suyama, J. Tachi, T. Takagi, C. Takaori, M. Takenaka, T. Tamai, K. Tanaka, Y. Tanaka, K. Tane, M. Taniura, N. Tatsuda, Y. Teramoto, K. Teranaka, S. Teranishi, J. Terasaki, K. Toki, K. Tsuji, Y. Tsuji, T. Tsunetoshi, K. Ujino, S. Umeki, N. Wakagi, N. Wakaki, K. Yamaguchi, Y. Yamamoto, S. Yanagitani, M. Yoshida, H. Yoshimoto, H. Yoshioka, H. Ikeda, M. Matsumoto, K. Nagae, M. Nishiyama, K. Noda, M. Ohga, M. Akui, H. Aoki, J. Arafune, M. Arai, T. Arai, I. Asami, K. Eguchi, T. Fujino, H. Fujinuma, H. Fukata, J. Fukuda, T. Hamasaki, M. Haneda, I. Hisauchi, T. Hogi, M. Ichikawa, T. Iijima, H. Inoue, Y. Inoue, T. Kakinuma, H. Kanai, U. Kaneko, T. Kano, T. Katsumi, T. Kawashima, K. Kogure, O. Komuro, Y. Kubouchi, N. Kujirai, K. Kurokawa, T. Lee, K. Maeda, T. Majima, Y. Maruyama, S. Mashiba, K. Mashiko, K. Matsumoto, M. Matsuzawa, Y. Mitsugi, J. Morita, C. Nakajima, Y. Nakazato, Y. Nashida, H. Nasuhara, Y. Numajiri, T. Ogasawara, T. Okudaira, I. Osawa, N. Otani, A. Otsuka, Y. Ozawa, T. Sakai, Y. Sakai, K. Shimizu, T. Shinozaki, M. Shirai, K. Shiroma, H. Shuto, H. Suzuki, A. Tada, M. Takagi, K. Takahashi, N. Takahashi, A. Taniguchi, Y. Tonegawa, M. Toyoda, T. Tsuchiya, M. Uchida, H. Uchino, H. Wada, O. Wada, H. Yoshioka, H. Horie, M. Ichikawa, K. Ikenoue, T. Kawashima, H. Mizuhara, S. Ono, S. Ishikawa, K. Kawakami, S. Yano, N. Kubota, A. Nakagawa, T. Shigemasa, S. Suwa, T. Akabane, M. Amagai, Y. Asanobu, S. Horinaka, T. Iijima, K. Kasai, T. Kataoka, M. Kobayashi, T. Masuda, I. Nakano, M. Namekawa, A. Numabe, A. Ono, K. Sakata, I. Taguchi, T. Tomotsune, S. Toyoda, M. Arizumi, Y. Morimoto, A. Ota, S. Sawada, K. Yata, H. Akita, T. Akitsu, K. Amemiya, M. Ando, N. Aoki, J. Aoyagi, T. Baba, T. Degawa, S. Eto, K. Fujimoto, H. Fukuda, T. Furukawa, I. Goto, A. Hachiya, Y. Hanatani, K. Hara, T. Haruta, K. Hasegawa, T. Hatano, M. Hayashi, T. Hirano, M. Hiratsuka, Y. Horikawa, T. Horiuchi, M. Hosoya, K. Ichikawa, K. Iguchi, H. Imai, K. Ishibashi, K. Ishida, Y. Ishii, S. Ishiwata, T. Iwama, H. Kadota, S. Kaku, Y. Kamisaka, R. Kanbara, T. Kanematsu, A. Kashiwagi, I. Kawa, B. Kawai, M. Kawai, S. Kiuchi, T. Kiyozuka, S. Koba, H. Kobayashi, K. Koike, H. Kojima, E. Koshibu, Y. Koshibu, I. Kubo, K. Kuga, T. Kushiro, S. Miyakata, M. Miyakawa, F. Miyoshi, Y. Mochida, N. Moriyama, T. Myojo, M. Nagashima, H. Nakada, T. Nakai, T. Nakamura, Y. Nakaya, M. Nishizawa, S. Nishizawa, K. Oba, Y. Obu, N. Ohara, M. Okazaki, Y. Okazaki, K. Okumura, T. Ono, Y. Osamura, M. Otsuka, M. Ouchi, N. Sakamoto, Y. Sakata, S. Saneshige, M. Sasajima, T. Satoi, Y. Sengoku, K. Shibuya, H. Shimizu, K. Shimokado, M. Shoji, H. Tabata, A. Takahashi, H. Takakura, T. Takao, M. Taya, H. Tomonari, T. Tsunematsu, A. Uehata, T. Umezawa, H. Usui, T. Watanabe, Y. Yajima, F. Yamada, K. Yamada, A. Yamaguchi, T. Yamaguchi, K. Yamamoto, M. Yamamoto, T. Hamada, I. Hisatome, K. Arita, M. Arita, E. Doi, H. Furuta, T. Hano, T. Hashizume, A. Hibino, N. Kodama, A. Saika, J. Ueda, T. Fujita, T. Ito, M. Sakano, T. Sugawara, H. Tachibana, H. Toda, S. Fujimoto, T. Furui, Y. Hadano, T. Kaneko, A. Kawabata, S. Kawamoto, M. Mezuki, M. Mochizuki, M. Nakatsuka, S. Ono, N. Tahara, M. Kuroda, H. Manabe, Combinations of olmesartan and a calciumchannel blocker or a diuretic inelderly hypertensive patients
A randomized, controlled trial, Journal of hypertension, 10.1097/HJH.0000000000000281, 32, 10, 2054-2063, 2014.10, Objective: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, openlabel, blinded endpoint trial. Methods: Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140mmHg and/or DBP at least 90mmHg with antihypertensive treatment, or SBP at least 160mmHg and/or DBP at least 100mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years. Results: Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65- 1.07, P=0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38-1.02, P=0.059, interaction P=0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P=0.046) experienced serious adverse events. Conclusion: Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic..
40. Shouji Matsushima, Junichi Sadoshima, The role of sirtuins in cardiac disease, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00053.2015, 309, 9, H1375-H1389, 2015, Modification of histones is one of the important mechanisms of epigenetics, in which genetic control is determined by factors other than an individual’s DNA sequence. Sirtuin family proteins, which are class III histone deacetylases, were originally identified as gene silencers that affect the mating type of yeast, leading to the name “silent mating-type information regulation 2” (SIR2). They are characterized by their requirement of nicotinamide adenine dinucleotide for their enzyme activity, unlike other classes of histone deacetylases. Sirtuins have been traditionally linked to longevity and the beneficial effects of calorie restriction and DNA damage repair. Recently, sirtuins have been shown to be involved in a wide range of physiological and pathological processes, including aging, energy responses to low calorie availability, and stress resistance, as well as apoptosis and inflammation. Sirtuins can also regulate mitochondrial biogenesis and circadian clocks. Seven sirtuin family proteins (Sirt1-7) have been identified as mammalian SIR2 orthologs, localized in different subcellular compartments, namely, the cytoplasm (Sirt1, 2), the mitochondria (Sirt3, 4, 5), and the nucleus (Sirt1, 2, 6, 7). Sirt1 is evolutionarily close to yeast SIR2 and has been the most intensively investigated in the cardiovascular system. Endogenous Sirt1 plays a pivotal role in mediating the cell death/survival process and has been implicated in the pathogenesis of cardiovascular disease. Downregulation of Sirt2 is protective against ischemic-reperfusion injury. Increased Sirt3 expression has been shown to correlate with longevity in humans. In addition, Sirt3 protects cardiomyocytes from aging and oxidative stress and suppresses cardiac hypertrophy. Sirt6 has also recently been demonstrated to attenuate cardiac hypertrophy, and Sirt7 is known to regulate apoptosis and stress responses in the heart. On the other hand, the roles of Sirt4 and Sirt5 in the heart remain largely uncharacterized..
41. Tomoyasu Kadoguchi, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Takaaki Furihata, Tsuneaki Homma, Yoshihiro Masaki, Wataru Mizushima, Mikito Nishikawa, Masashige Takahashi, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle, Experimental Physiology, 10.1113/expphysiol.2014.084095, 100, 3, 312-322, 2015.03, New findings: What is the central question of this study? Does angiotensin II directly induce skeletal muscle abnormalities? What is the main finding and its importance? Angiotensin II induces skeletal muscle abnormalities and reduced exercise capacity. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest early, while muscle atrophy is seen later. Thus, angiotensin II may play an important role in the skeletal muscle abnormalities observed in a wide variety of diseases. Skeletal muscle abnormalities, such as mitochondrial dysfunction, a decreased percentage of oxidative fibres and atrophy, are the main cause of reduced exercise capacity observed in ageing and various diseases, including heart failure. The renin-angiotensin system, particularly angiotensin II (Ang II), is activated in the skeletal muscle in these conditions. Here, we examined whether Ang II could directly induce these skeletal muscle abnormalities and investigated their time course. Angiotensin II (1000 ng kg-1 min-1) or vehicle was administered to male C57BL/6J mice (10-12 weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4 weeks. Angiotensin II significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4 weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4 weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with Ang II. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with Ang II at 1 and 4 weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complex I and complex III activities were significantly decreased in the skeletal muscle from mice treated Ang II at 1 and 4 weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that type I fibres were decreased and type IIb fibres increased in mice treated with Ang II at 1 week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with Ang II at 4 weeks. Thus, Ang II could directly induce the abnormalities in skeletal muscle function and structure..
42. Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takashi Yokota, Shouji Matsushima, Shingo Takada, Tomoyasu Kadoguchi, Koji Oba, Koichi Okita, Hiroyuki Tsutsui, Serum brain-derived neurotropic factor level predicts adverse clinical outcomes in patients with heart failure, Journal of Cardiac Failure, 10.1016/j.cardfail.2015.01.003, 21, 4, 300-306, 2015.04, Background Brain-derived neurotropic factor (BDNF) is involved in cardiovascular diseases as well as skeletal muscle energy metabolism and depression. We investigated whether serum BDNF level was associated with prognosis in patients with heart failure (HF). Methods and Results We measured the serum BDNF level in 58 patients with HF (59.2 ± 13.7 years old, New York Heart Association functional class I-III) at baseline, and adverse events, including all cardiac deaths and HF rehospitalizations, were recorded during the median follow-up of 20.3 months. In a univariate analysis, serum BDNF levels were significantly associated with peak oxygen capacity (β = 0.547; P =.003), anaerobic threshold (β = 0.929; P =.004), and log minute ventilation/carbon dioxide production slope (β = -10.15; P =.005), but not Patient Health Questionnaire scores (β = -0.099; P =.586). A multivariate analysis demonstrated that serum BDNF level was an independent prognostic factor of adverse events (hazard ratio 0.41, 95% confidence interval 0.20-0.84; P =.003). The receiver operating characteristic curve demonstrated that low levels of BDNF (<17.4 ng/mL) were associated with higher rates of adverse events compared with high levels of BDNF (≥17.4 ng/mL; log rank test: P <.001). Conclusions Decreased serum BDNF levels were significantly associated with adverse outcomes in HF patients, suggesting that these levels can be a useful prognostic biomarker..
43. Mikito Nishikawa, Naoki Ishimori, Shingo Takada, Akimichi Saito, Tomoyasu Kadoguchi, Takaaki Furihata, Arata Fukushima, Shouji Matsushima, Takashi Yokota, Shintaro Kinugawa, Hiroyuki Tsutsui, AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress, Nephrology Dialysis Transplantation, 10.1093/ndt/gfv103, 30, 6, 934-942, 2015.06, Background. Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD. Methods. Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress. Results. Plasma IS levels were significantly increased in CKD compared with Sham (1.05 ± 0.11 versus 0.21 ± 0.03 mg/dL, P <0.05), which was significantly ameliorated in CKD + AST-120 (0.41 ± 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 ± 17 versus 427 ± 36 m, P <0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 ± 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P)H oxidase activity. Conclusions. The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD..
44. Shintaro Kinugawa, Shingo Takada, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Skeletal muscle abnormalities in heart failure, International heart journal, 10.1536/ihj.15-108, 56, 5, 475-484, 2015.09, Exercise capacity is lowered in patients with heart failure, which limits their daily activities and also reduces their quality of life. Furthermore, lowered exercise capacity has been well demonstrated to be closely related to the severity and prognosis of heart failure. Skeletal muscle abnormalities including abnormal energy metabolism, transition of myofibers from type I to type II, mitochondrial dysfunction, reduction in muscular strength, and muscle atrophy have been shown to play a central role in lowered exercise capacity. The skeletal muscle abnormalities can be classified into the following main types: 1) low endurance due to mitochondrial dysfunction; and 2) low muscle mass and muscle strength due to imbalance of protein synthesis and degradation. The molecular mechanisms of these skeletal muscle abnormalities have been studied mainly using animal models. The current review including our recent study will focus upon the skeletal muscle abnormalities in heart failure..
45. Yanfei Yang, Dominic P. Del Re, Noritsugu Nakano, Sebastiano Sciarretta, Peiyong Zhai, Jiyeon Park, Danish Sayed, Akihiro Shirakabe, Shoji Matsushima, Yongkyu Park, Bin Tian, Maha Abdellatif, Junichi Sadoshima, MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival, Circulation research, 10.1161/CIRCRESAHA.115.306624, 117, 10, 891-904, 2015.10, Rationale: In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional cofactor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear. Objectives: We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP on promotion of survival and hypertrophy in cardiomyocytes. Methods and Results: Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Downregulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion injury, whereas suppression of miR-206 exacerbated ischemia/reperfusion injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates Forkhead box protein P1 expression in cardiomyocytes and overexpression of Forkhead box protein P1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that Forkhead box protein P1 is a functional target of miR-206. Conclusions: YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing Forkhead box protein P1 in cardiomyocytes..
46. Masashige Takahashi, Shintaro Kinugawa, Shingo Takada, Kagami Hirabayashi, Takashi Yokota, Shouji Matsushima, Akimichi Saito, Koichi Okita, Hiroyuki Tsutsui, Low-intensity exercise under ischemic conditions enhances metabolic stress in patients with heart failure, International Journal of Cardiology, 10.1016/j.ijcard.2015.08.022, 201, 142-144, 2015.10.
47. Shingo Takada, Shintaro Kinugawa, Shouji Matsushima, Daisuke Takemoto, Takaaki Furihata, Wataru Mizushima, Arata Fukushima, Takashi Yokota, Yoshiko Ono, Hiroshi Shibata, Koichi Okita, Hiroyuki Tsutsui, Sesamin prevents decline in exercise capacity and impairment of skeletal muscle mitochondrial function in mice with high-fat diet-induced diabetes, Experimental Physiology, 10.1113/EP085251, 100, 11, 1319-1330, 2015.11, We previously reported that exercise capacity and skeletal muscle mitochondrial function in diabetic mice were impaired, in association with the activation of NAD(P)H oxidase. It has been reported that sesamin inhibits NAD(P)H oxidase-induced superoxide production. Therefore, we examined whether the antioxidant sesamin could prevent a decline in exercise capacity in mice with high-fat diet (HFD)-induced diabetes. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated or not with sesamin (0.2%) to yield the following four groups: ND, ND+Sesamin, HFD and HFD+Sesamin (n = 10 each). After 8 weeks, body weight, fat weight, blood glucose, insulin, triglyceride, total cholesterol and fatty acid were significantly increased in HFD compared with ND mice. Sesamin prevented the increases in blood insulin and lipid levels in HFD-fed mice, but did not affect the plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in HFD mice, but almost completely recovered in HFD+Sesamin mice. Citrate synthase activity was significantly decreased in the skeletal muscle of HFD mice, and these decreases were also inhibited by sesamin. Superoxide anion and NAD(P)H oxidase activity were significantly increased in HFD mice compared with the ND mice and were ameliorated by sesamin. Sesamin prevented the decline in exercise capacity in HFD-induced diabetic mice via maintenance of mitochondrial function, fat oxidation and attenuation of oxidative stress in the skeletal muscle. Our data suggest that sesamin may be useful as a novel agent for the treatment of diabetes mellitus..
48. Shouji Matsushima, Daniela Zablocki, Hiroyuki Tsutsui, Junichi Sadoshima, Poldip2 negatively regulates matrix synthesis at focal adhesions, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2016.03.001, 94, 10-12, 2016.05.
49. Arata Fukushima, Shintaro Kinugawa, Shingo Takada, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Masaya Tsuda, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice, European Journal of Pharmacology, 10.1016/j.ejphar.2016.03.022, 779, 147-156, 2016.05, Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress..
50. Takaaki Furihata, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Masashige Takahashi, Tsuneaki Homma, Yoshihiro Masaki, Masaya Tsuda, Junichi Matsumoto, Wataru Mizushima, Shouji Matsushima, Takashi Yokota, Hiroyuki Tsutsui, The experimental model of transition from compensated cardiac hypertrophy to failure created by transverse aortic constriction in mice, IJC Heart and Vasculature, 10.1016/j.ijcha.2016.03.007, 11, 24-28, 2016.06, Background: Transverse aortic constriction (TAC) operation is used as an experimental model of left ventricular (LV) hypertrophy and LV failure in mice. The severity of LV remodeling or failure may depend on the degree of TAC, but is variable among operated animals. Therefore, we tried to identify the optimal diameter of TAC to create this model with ease and high reproducibility. Methods and results: To produce TAC in C57BL/6J mice (7-9 weeks, body weight 19-26 g, n = 109), a 7-0 nylon suture ligature was tightly tied around the transverse aorta against needles with 3 different diameters (mm); 0.40, 0.385 and 0.375. LV wall thickness, end-diastolic dimension, fractional shortening were measured by echocardiography. At 4 weeks after TAC, no mouse with the 0.400 mm gauge progressed in LV failure. The 0.385 mm pin gauge mouse kept a more survival rate compared with the 0.375 mm (59% vs 48%), representing same efficient in LV failure. With the 0.385 mm pin gauge, hearts of mice remained LV hypertrophy at 1 week after TAC, followed by LV failure at 4 weeks. Conclusion: TAC with the diameter of 0.385 mm can effectively induce the transition from LV hypertrophy to failure in mice with relatively preserved survival..
51. Tadao Aikawa, Masanao Naya, Osamu Manabe, Masahiko Obara, Shouji Matsushima, Nagara Tamaki, Hiroyuki Tsutsui, Incidental focal myocardial 18F-FDG uptake indicating asymptomatic coronary artery disease, Journal of Nuclear Cardiology, 10.1007/s12350-015-0258-5, 23, 3, 596-598, 2016.06.
52. Shouji Matsushima, Junya Kuroda, Peiyong Zhai, Tong Liu, Shohei Ikeda, Narayani Nagarajan, Shin Ichi Oka, Takashi Yokota, Shintaro Kinugawa, Chiao Po Hsu, Hong Li, Hiroyuki Tsutsui, Junichi Sadoshima, Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling, Journal of Clinical Investigation, 10.1172/JCI85624, 126, 9, 3403-3416, 2016.09, NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O2 - production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling..
53. Shingo Takada, Yoshihiro Masaki, Shintaro Kinugawa, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Masashige Takahashi, Shinichi Harashima, Shouji Matsushima, Takashi Yokota, Shinya Tanaka, Koichi Okita, Hiroyuki Tsutsui, Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling, Cardiovascular research, 10.1093/cvr/cvw182, 111, 4, 338-347, 2016.09, Aims Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model after myocardial infarction (MI). Methods and results MI was created in male C57BL/6J mice by ligating the left coronary artery, and a sham operation was performed in other mice. The mice were then divided into two groups according to the treatment with or without a DPP-4 inhibitor, MK-0626 [1 mg/kg body weight (BW)/day] provided in the diet. Four weeks later, the exercise capacity evaluated by treadmill test was revealed to be limited in the MI mice, and it was ameliorated in the MI + MK-0626 group without affecting the infarct size or cardiac function. The citrate synthase activity, mitochondrial oxidative phosphorylation capacity, supercomplex formation, and their quantity were reduced in the skeletal muscle from the MI mice, and these decreases were normalized in the MI + MK-0626 group, in association with the improvement of mitochondrial biogenesis. Immunohistochemical staining also revealed that a shift toward the fast-twitch fibre type in the MI mice was also reversed by MK-0626. Favourable effects of MK-0626 were significantly inhibited by treatment of GLP-1 antagonist, Exendin-(9-39) (150 pmol/kg BW/min, subcutaneous osmotic pumps) in MI + MK-0626 mice. Similarly, exercise capacity and mitochondrial function were significantly improved by treatment of GLP-1 agonist, Exendin-4 (1 nmol/kg/BW/h, subcutaneous osmotic pumps). Conclusions A DPP-4 inhibitor may be a novel therapeutic agent against the exercise intolerance seen in HF patients by improving the mitochondrial biogenesis in their skeletal muscle..
54. Wataru Mizushima, Hidehisa Takahashi, Masashi Watanabe, Shintaro Kinugawa, Shouji Matsushima, Shingo Takada, Takashi Yokota, Takaaki Furihata, Junichi Matsumoto, Masaya Tsuda, Ikuru Chiba, Shun Nagashima, Shigeru Yanagi, Masaki Matsumoto, Keiichi I. Nakayama, Hiroyuki Tsutsui, Shigetsugu Hatakeyama, The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2016.09.013, 100, 43-53, 2016.11, A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction. Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure. Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure..
55. Takashi Yokota, Shintaro Kinugawa, Kagami Hirabayashi, Tadashi Suga, Shingo Takada, Masashi Omokawa, Tomoyasu Kadoguchi, Masashige Takahashi, Arata Fukushima, Shouji Matsushima, Mayumi Yamato, Koichi Okita, Hiroyuki Tsutsui, Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome, Journal of Diabetes Investigation, 10.1111/jdi.12606, 8, 4, 535-541, 2017.07, Aims/Introduction: Low aerobic capacity is a strong and independent predictor of all-cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole-body aerobic capacity and skeletal muscle energy metabolism in MetS patients. Materials and Methods: A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole-body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high-energy phosphates in the calf muscle during plantar-flexion exercise were measured using 1proton- and 31phosphorus magnetic resonance spectroscopy, respectively. Results: Pioglitazone significantly increased peak oxygen uptake (25.1 ± 4.9 mL/kg/min pretreatment vs 27.2 ± 3.9 mL/kg/min post- treatment, P < 0.05) and anaerobic threshold (12.7 ± 1.9 mL/kg/min pretreatment vs 13.6 ± 1.6 mL/kg/min post-treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high-energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment. Conclusions: Pioglitazone significantly improved the MetS patients’ whole-body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole-body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle..
56. Yasuki Nakada, Rika Kawakami, Shouji 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, 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..
57. Soichiro Ikeda, Shouji Matsushima, Kosuke Okabe, Masataka Ikeda, Akihito Ishikita, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Masashi Sada, Hiroko Deguchi, Sachio Morimoto, Tomomi Ide, Hiroyuki Tsutsui, Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway, Scientific reports, 10.1038/s41598-019-46367-6, 9, 1, 2019.12, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-kappa B (NF-κB) play crucial roles in pathogenesis of doxorubicin (DOX)-induced cardiomyopathy. Their activities are regulated by intracellular Ca2+. We hypothesized that blockade of L-type Ca2+ channel (LTCC) could attenuate DOX-induced cardiomyopathy by regulating CaMKII and NF-κB. DOX activated CaMKII and NF-κB through their phosphorylation and increased cleaved caspase 3 in cardiomyocytes. Pharmacological blockade or gene knockdown of LTCC by nifedipine or small interfering RNA, respectively, suppressed DOX-induced phosphorylation of CaMKII and NF-κB and apoptosis in cardiomyocytes, accompanied by decreasing intracellular Ca2+ concentration. Autocamtide 2-related inhibitory peptide (AIP), a selective CaMKII inhibitor, inhibited DOX-induced phosphorylation of NF-κB and cardiomyocyte apoptosis. Inhibition of NF-κB activity by ammonium pyrrolidinedithiocarbamate (PDTC) suppressed DOX-induced cardiomyocyte apoptosis. DOX-treatment (18 mg/kg via intravenous 3 injections over 1 week) increased phosphorylation of CaMKII and NF-κB in mouse hearts. Nifedipine (10 mg/kg/day) significantly suppressed DOX-induced phosphorylation of CaMKII and NF-κB and cardiomyocyte injury and apoptosis in mouse hearts. Moreover, it attenuated DOX-induced left ventricular dysfunction and dilatation. Our findings suggest that blockade of LTCC attenuates DOX-induced cardiomyocyte apoptosis via suppressing intracellular Ca2+ elevation and activation of CaMKII-NF-κB pathway. LTCC blockers might be potential therapeutic agents against DOX-induced cardiomyopathy..
58. Hiroko Deguchi, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Keita Saku, Shouji Matsushima, Hiroyuki Tsutsui, Roxadustat markedly reduces myocardial ischemia reperfusion injury in mice, Circulation Journal, 10.1253/circj.CJ-19-1039, 84, 6, 1028-1033, 2020, Background: Ischemic preconditioning (IPC) is an effective procedure to protect against ischemia/reperfusion (I/R) injury. Hypoxia-inducible factor-1α (Hif-1α) is a key molecule in IPC, and roxadustat (RXD), a first-in-class prolyl hydroxylase domain-containing protein inhibitor, has been recently developed to treat anemia in patients with chronic kidney disease. Thus, we investigated whether RXD pretreatment protects against I/R injury. Methods and Results: RXD pretreatment markedly reduced the infarct size and suppressed plasma creatinine kinase activity in a murine I/R model. Analysis of oxygen metabolism showed that RXD could produce ischemic tolerance by shifting metabolism from aerobic to anaerobic respiration. Conclusions: RXD pretreatment may be a novel strategy against I/R injury..
59. Hidetaka Kaku, Kouta Funakoshi, Tomomi Ide, Takeo Fujino, Shouji Matsushima, Kisho Ohtani, Taiki Higo, Michikazu Nakai, Yoko Sumita, Kunihiro Nishimura, Yoshihiro Miyamoto, Toshihisa Anzai, Hiroyuki Tsutsui, Impact of hospital practice factors on mortality in patients hospitalized for heart failure in Japan ― an analysis of a large number of health records from a nationwide claims-based database, the JROAD-DPC ―, Circulation Journal, 10.1253/circj.CJ-19-0759, 84, 5, 742-753, 2020, Background: An inverse relationship exists between hospital case volume and mortality in patients with heart failure (HF). However, hospital performance factors associated with mortality in HF patients have not been examined. We aimed to identify these using exploratory factor analysis and assess the relationship between these factors and 7-day, 30-day, and in-hospital mortality among HF patients in Japan. Methods and Results: We analyzed the records of 198,861 patients admitted to 683 certified hospitals of the Japanese Circulation Society between 2012 and 2014. Records were obtained from the nationwide database of the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). Using exploratory factor analysis, 90 hospital survey items were grouped into 5 factors, according to their collinearity: “Interventional cardiology”, “Cardiovascular surgery”, “Pediatric cardiology”, “Electrophysiology” and “Cardiac rehabilitation”. Multivariable logistic regression analysis was performed to determine the association between these factors and mortality. The 30-day mortality was 8.0%. Multivariable logistic regression analysis showed the “Pediatric cardiology” (odds ratio (OR) 0.677, 95% confidence interval [CI]: 0.628–0.729, P<0.0001), “Electrophysiology” (OR 0.876, 95% CI: 0.832–0.923, P<0.0001), and “Cardiac rehabilitation” (OR 0.832, 95% CI: 0.792–0.873, P<0.0001) factors were associated with lower mortality. In contrast, “Interventional cardiology” (OR 1.167, 95% CI: 1.070–1.272, P<0.0001) was associated with higher mortality. Conclusions: Hospital factors, including various cardiovascular therapeutic practices, may be associated with the early death of HF patients..
60. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Taiki Higo, Miyuki Tsuchihashi-Makaya, Hiroyuki Tsutsui, Spironolactone use is associated with improved outcomes in heart failure with mid-range ejection fraction, ESC Heart Failure, 10.1002/ehf2.12571, 7, 1, 339-347, 2020.02, Aims: Spironolactone has been shown to improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). We investigated whether the discharge use of spironolactone could be associated with better long-term outcomes among patients with HF with mid-range EF (HFmrEF). Methods and results: We analysed HFmrEF (left ventricular EF 40–49%) patients enrolled in the Japanese Cardiac Registry of Heart Failure in Cardiology, which prospectively studied the clinical characteristics, treatments, and long-term outcomes of patients hospitalized due to HF. Patients were divided into two groups according to the use of spironolactone at discharge. The primary outcome was a composite of all-cause death or HF rehospitalization. A total of 457 patients had HFmrEF. The mean age was 69.3 years and 286 (62.6%) were male. Among them, spironolactone was prescribed at discharge in 158 patients (34.6%). Chronic kidney disease (7.6% vs. 16.8%, P = 0.007) was less prevalent and loop diuretics (89.2% vs. 70.2%, P < 0.001) were more often prescribed in patients with spironolactone. During a mean follow-up of 2.2 years, patients with spironolactone had a lower incidence rate of the primary outcome than those without it (171.5 vs. 278.8 primary outcome per 1000 patient-years, incidence rate ratio 0.61, 95% confidence interval 0.44–0.86; P = 0.004). After multivariable adjustment, spironolactone use at discharge was associated with a significant reduction in the composite of all-cause death or HF rehospitalization (adjusted hazard ratio 0.63, 95% confidence interval 0.44–0.90, P = 0.010). Conclusions: Among patients with HF hospitalized for HFmrEF, spironolactone use at discharge was associated with better long-term outcomes..
61. Daisuke Yakabe, Shouji Matsushima, Saori Uchino, Kisho Ohtani, Tomomi Ide, Taiki Higo, Hiroyuki Tsutsui, Left ventricular noncompaction with multiple thrombi in apical aneurysm, Internal Medicine, 10.2169/internalmedicine.3489-19, 59, 3, 377-381, 2020.02, A 44-year-old man was admitted to our hospital due to heart failure. Transthoracic echocardiography demonstrated global hypokinesis with an ejection fraction of 25%, prominent trabeculation and deep intertrabecular recesses, and apical aneurysm with multiple thrombi (10×13 mm in the inferior wall, 15×8 mm in the anterior wall). Cardiac magnetic resonance imaging showed an increased ratio of noncompacted (NC) to compacted (C) myocardium (NC/C ratio >2.3) and apical aneurysm. Coronary angiography revealed no significant stenosis. He was therefore diagnosed with left ventricular noncompaction complicated by apical aneurysm. Four weeks after starting anticoagulation, the multiple apical thrombi disappeared without clinical signs of embolism..
62. Kosuke Okabe, Shouji Matsushima, Soichiro Ikeda, Masataka Ikeda, Akihito Ishikita, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Masashi Sada, Hiroko Deguchi, Keisuke Shinohara, Tomomi Ide, Hiroyuki Tsutsui, DPP (dipeptidyl peptidase)-4 inhibitor attenuates ANG II (angiotensin II)–induced cardiac hypertrophy via GLP (glucagon-like peptide)-1–dependent suppression of NOx (nicotinamide adenine dinucleotide phosphate oxidase) 4-HDAC (histone deacetylase) 4 pathway, Hypertension, 10.1161/HYPERTENSIONAHA.119.14400, 991-1001, 2020.04, —Nox4 (NADPH [Nicotinamide adenine dinucleotide phosphate] oxidase 4) is a major source of oxidative stress and is intimately involved in cardiac hypertrophy. DPP (Dipeptidyl peptidase)-4 inhibitor has been reported to regulate Nox4 expression in adipose tissues. However, its effects on Nox4 in cardiac hypertrophy are still unclear. We investigated whether DPP-4 inhibitor could ameliorate cardiac hypertrophy by regulating Nox4 and its downstream targets. Ang II (Angiotensin II; 1.44 mg/kg per day) or saline was continuously infused into C57BL/6J mice with or without teneligliptin (a DPP-4 inhibitor, 30 mg/kg per day) in the drinking water for 1 week. Teneligliptin significantly suppressed plasma DPP-4 activity without any significant changing aortic blood pressure or metabolic parameters such as blood glucose and insulin levels. It attenuated Ang II–induced increases in left ventricular wall thickness and the ratio of heart weight to body weight. It also significantly suppressed Ang II–induced increases in Nox4 mRNA, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4 (histone deacetylase 4), a downstream target of Nox4 and a crucial suppressor of cardiac hypertrophy, in the heart. Exendin-3 (150 pmol/kg per minute), a GLP-1 (glucagon-like peptide 1) receptor antagonist, abrogated these inhibitory effects of teneligliptin on Nox4, 4-hydroxy-2-nonenal, phosphorylation of HDAC4, and cardiac hypertrophy. In cultured neonatal cardiomyocytes, exendin-4 (100 nmol/L, 24 hours), a GLP-1 receptor agonist, ameliorated Ang II–induced cardiomyocyte hypertrophy and decreased in Nox4, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4. Furthermore, exendin-4 prevented Ang II–induced decrease in nuclear HDAC4 in cardiomyocytes. In conclusion, GLP-1 receptor stimulation by DPP-4 inhibitor can attenuate Ang II–induced cardiac hypertrophy by suppressing of the Nox4-HDAC4 axis in cardiomyocytes..
63. Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Hiroko Deguchi, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui, Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity, JCI Insight, 10.1172/jci.insight.132747, 5, 9, 2020.05, Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicininduced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity..
64. Yakabe D, Matsushima S, Uchino S, Ohtani K, Ide T, Higo T, Tsutsui H, Left Ventricular Noncompaction with Multiple Thrombi in Apical Aneurysm., 2019.08.
65. Ikeda S, Matsushima S, Okabe K, Ikeda M, Ishikita A, Tadokoro T, Enzan N, Yamamoto T, Sada M, Deguchi H, Morimoto S, Ide T, Tsutsui H., Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway., Sci Rep, 2019.06.
66. Matsushima S, Kaku H, Enzan N, Ide T, Higo T, Tsuchihashi-Makaya M, Tsutsui H, Electrocardiographic Left Ventricular Hypertrophy is Independently Associated with Better Long-Term Outcomes in Dilated Cardiomyopathy Patients., Circ Rep, 2019.06.
67. Yokota T, Kinugawa S, Hirabayashi K, Suga T, Takada S, Omokawa M, Kadoguchi T, Takahashi M, Fukushima A, Matsushima S, Yamato M, Okita K, Tsutsui H., Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome., J Diabetes Investig, 8(4):535-541, 2017.06.
68. 松島 将士, Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. , Journal of Clinical Investigation , 126, 9, 3403-34-16, 2016.09.