| 1. |
Ko Abe, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Shun Furusawa, Yoshitomo Tsutsui, Ryo Miyake, Kosei Ishimaru, Masatsugu Watanabe, Shouji Matsushima, Tomoko Koumura, Ken-Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui, Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis., Science signaling, 10.1126/scisignal.abn8017, 15, 758, eabn8017, 2022.11, Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.. |
| 2. |
Masataka Ikeda, Tomomi Ide, Shouji Matsushima, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Tomonori Tadokoro, Masashi Sada, Ko Abe, Midori Sato, Akiko Hanada, Shinobu Arai, Kisho Ohtani, Atsushi Nonami, Shinichi Mizuno, Sachio Morimoto, Shinichiro Motohashi, Koichi Akashi, Masaru Taniguchi, Hiroyuki Tsutsui, Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model., Circulation. Heart failure, 10.1161/CIRCHEARTFAILURE.122.009366, 15, 12, e009366, 2022.10, BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated. METHODS: Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin TΔK210/ΔK210 with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. RESULTS: The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-β signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 (Angpt1) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-β-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated Angpt1 expression in cardiomyocytes via Stat1. CONCLUSIONS: Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM.. |
| 3. |
Hiroko Deguchi Miyamoto, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Shun Furusawa, Ko Abe, Kosei Ishimaru, Nobuyuki Enzan, Masashi Sada, Taishi Yamamoto, Shouji Matsushima, Tomoko Koumura, Ken-Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui, Iron Overload via Heme Degradation in the Endoplasmic Reticulum Triggers Ferroptosis in Myocardial Ischemia-Reperfusion Injury., JACC. Basic to translational science, 10.1016/j.jacbts.2022.03.012, 7, 8, 800-819, 2022.08, Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron overload and excessive lipid peroxides, is reportedly involved in I/R injury. However, its significance and mechanistic basis remain unclear. Here, we show that glutathione peroxidase 4 (GPx4), a key endogenous suppressor of ferroptosis, determines the susceptibility to myocardial I/R injury. Importantly, ferroptosis is a major mode of cell death in I/R injury, distinct from mitochondrial permeability transition (MPT)-driven necrosis. This suggests that the use of therapeutics targeting both modes is an effective strategy to further reduce the infarct size and thereby ameliorate cardiac remodeling after I/R injury. Furthermore, we demonstrate that heme oxygenase 1 up-regulation in response to hypoxia and hypoxia/reoxygenation degrades heme and thereby induces iron overload and ferroptosis in the endoplasmic reticulum (ER) of cardiomyocytes. Collectively, ferroptosis triggered by GPx4 reduction and iron overload in the ER is distinct from MPT-driven necrosis in both in vivo phenotype and in vitro mechanism for I/R injury. The use of therapeutics targeting ferroptosis in conjunction with cyclosporine A can be a promising strategy for I/R injury.. |
| 4. |
Tomonori Tadokoro, Masataka Ikeda, Ko Abe, Tomomi Ide, Hiroko Deguchi Miyamoto, Shun Furusawa, Kosei Ishimaru, Masatsugu Watanabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken-Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui, Ethoxyquin is a competent radical-trapping antioxidant for preventing ferroptosis in doxorubicin cardiotoxicity., Journal of cardiovascular pharmacology, 10.1097/FJC.0000000000001328, 2022.07, ABSTRACT: Doxorubicin (DOX) is an effective anti-cancer agent for various malignancies. Nevertheless, it has a side effect of cardiotoxicity, referred to as doxorubicin-induced cardiomyopathy (DIC), that is associated with a poorer prognosis. This cardiotoxicity limits the clinical use of DOX as a therapeutic agent for malignancies. Recently, ferroptosis, a form of regulated cell death induced by the accumulation of lipid peroxides, has been recognized as a major pathophysiology of DIC. Ethoxyquin is a lipophilic antioxidant widely used for food preservation and thus may be a potential therapeutic drug for preventing DIC. However, the efficacy of ethoxyquin against ferroptosis and DIC remains to be fully elucidated. Here, we investigated the inhibitory action of ethoxyquin against GPx4-deficient ferroptosis and its therapeutic efficacy against DOX-induced cell death in cultured cardiomyocytes and cardiotoxicity in a murine model of DIC. In cultured cardiomyocytes, ethoxyquin treatment effectively prevented GPx4-deficient ferroptosis. Ethoxyquin also prevented DOX-induced cell death, accompanied by the suppression of malondialdehyde (MDA) and mitochondrial lipid peroxides, which were induced by DOX. Furthermore, ethoxyquin significantly prevented DOX-induced cell death without any suppression of caspase cleavages representing apoptosis. In DIC mice, ethoxyquin treatment ameliorated cardiac impairments, such as contractile dysfunction and myocardial atrophy, and lung congestion. Ethoxyquin also suppressed serum lactate dehydrogenase and creatine kinase activities, decreased the levels of lipid peroxides such as MDA and acrolein, inhibited cardiac fibrosis, and reduced TUNEL-positive cells in the hearts of DIC mice. Collectively, ethoxyquin is a competent antioxidant for preventing ferroptosis in DIC and can be its prospective therapeutic drug.. |
| 5. |
Yuta Nagatomi, Tomomi Ide, Tae Higuchi, Tomoyuki Nezu, Takeo Fujino, Takeshi Tohyama, Takuya Nagata, Taiki Higo, Toru Hashimoto, Shouji Matsushima, Keisuke Shinohara, Tomiko Yokoyama, Aika Eguchi, Ayumi Ogusu, Masataka Ikeda, Yusuke Ishikawa, Fumika Yamashita, Shintaro Kinugawa, Hiroyuki Tsutsui, Home-based cardiac rehabilitation using information and communication technology for heart failure patients with frailty, ESC HEART FAILURE, 10.1002/ehf2.13934, 2022.05, Aims Cardiac rehabilitation (CR) is an evidence-based, secondary preventive strategy that improves mortality and morbidity rates in patients with heart failure (HF). However, the implementation and continuation of CR remains unsatisfactory, particularly for outpatients with physical frailty. This study investigated the efficacy and safety of a comprehensive home-based cardiac rehabilitation (HBCR) programme that combines patient education, exercise guidance, and nutritional guidance using information and communication technology (ICT).Methods and results This study was a single-centre, open-label, randomized, controlled trial. Between April 2020 and November 2020, 30 outpatients with chronic HF (New York Heart Association II-III) and physical frailty were enrolled. The control group (n = 15) continued with standard care, while the HBCR group (n = 15) also received comprehensive, individualized CR, including ICT-based exercise and nutrition guidance using ICT via a Fitbit (R) device for 3 months. The CR team communicated with each patient in HBCR group once a week via the application messaging tool and planned the training frequency and intensity of training individually for the next week according to each patient's symptoms and recorded pulse data during exercise. Dietitians conducted a nutritional assessment and then provided individual nutritional advice using the picture-posting function of the application. The primary outcome was the change in the 6 min walking distance (6MWD). The participants' mean age was 63.7 +/- 10.1 years, 53% were male, and 87% had non-ischaemic heart disease. The observed change in the 6MWD was significantly greater in the HBCR group (52.1 +/- 43.9 m vs. -4.3 +/- 38.8 m; P |
| 6. |
Inoue T, Ide T, Yamato M, Yoshida M, Tsutsumi T, Andou M, Utsumi H, Tsutsui H, Sunagawa K, Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction, Free radical research, 2009.01. |
| 7. |
Fatty acids increase the circulating levels of oxidative stress factors in mice with diet-induced obesity via redox changes of albumin. |
| 8. |
Tsutsumi T., Ide T., Yamato M., Andou M., Shiba T., Utsumi H., Sunagawa K, Effect of anaesthesia-induced alterations in haemodynamics on in vivo kinetics of nitroxyl probes in electron spin resonance spectroscopy., Free Radic Res., 305-311, 2008.04. |
| 9. |
Tsutsumi T, Ide T, Yamato M, Kudou W, Andou M, Hirooka Y, Utsumi H, Tsutsui H, Sunagawa K, Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction., Cardiovasc Res., 713-721, 2008.03. |
| 10. |
Matsushima S, Ide T, Yamato M, Matsusaka H, Hattori F, Ikeuchi M, Kubota T, Sunagawa K, Hasegawa Y, Kurihara T, Oikawa S, Kinugawa S, Tsutsui H., Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice., Circulation, 113(14):1779-86., 2006.04. |
| 11. |
Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T, Kubota T, Fujiwara T, Hamasaki N, Takeshita A, Sunagawa K, Tsutsui H., Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction., Circulation., 10.1161/CIRCULATIONAHA.104.524835, 112, 5, 683-690, 112(5):683-90. , 2005.08. |
| 12. |
Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes.. |
| 13. |
Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, Utsumi H, Hamasaki N, Takeshita A., Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction., 88(5):529-35.. |
