{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:46:37Z","timestamp":1790433997687,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,1,13]]},"abstract":"\n Background<\/jats:title>\n \n The\n homologous to the E6\u2010AP carboxyl terminus (HECT)<\/jats:styled-content>\n \u2013type ubiquitin E3 ligase\n ITCH<\/jats:styled-content>\n is an enzyme that plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin\u2010interacting protein (\n TXNIP<\/jats:styled-content>\n ) is a negative regulator of the thioredoxin system and an endogenous reactive oxygen species scavenger. In the present study, we focused on the functional role of ubiquitin E3 ligase\n ITCH<\/jats:styled-content>\n and its interaction with\n TXNIP<\/jats:styled-content>\n to elucidate the mechanism of cardiotoxicity induced by\n reactive oxygen species<\/jats:styled-content>\n , such as doxorubicin and hydrogen peroxide.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Protein interaction between\n TXNIP<\/jats:styled-content>\n and\n ITCH<\/jats:styled-content>\n in cardiomyocyte was confirmed by immunoprecipitation assays. Overexpression of\n ITCH<\/jats:styled-content>\n increased proteasomal\n TXNIP<\/jats:styled-content>\n degradation and augmented thioredoxin activity, leading to inhibition of\n reactive oxygen species<\/jats:styled-content>\n generation, p38\n MAPK<\/jats:styled-content>\n , p53, and subsequent intrinsic pathway cardiomyocyte apoptosis in\n reactive oxygen species<\/jats:styled-content>\n \u2013induced cardiotoxicity. Conversely, knockdown of\n ITCH<\/jats:styled-content>\n using small interfering\n RNA<\/jats:styled-content>\n inhibited\n TXNIP<\/jats:styled-content>\n degradation and resulted in a subsequent increase in cardiomyocyte apoptosis. Next, we generated a transgenic mouse with cardiac\u2010specific overexpression of\n ITCH<\/jats:styled-content>\n , called the\n ITCH<\/jats:styled-content>\n \u2010Tg mouse. The expression level of\n TXNIP<\/jats:styled-content>\n in the myocardium in\n ITCH<\/jats:styled-content>\n \u2010Tg mice was significantly lower than WT littermates. In\n ITCH<\/jats:styled-content>\n \u2010Tg mice, cardiac dysfunction and remodeling were restored compared with WT littermates after doxorubicin injection and myocardial infarction surgery. Kaplan\u2013Meier analysis revealed that\n ITCH<\/jats:styled-content>\n \u2010Tg mice had a higher survival rate than WT littermates after doxorubicin injection and myocardial infarction surgery.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We demonstrated, for the first time, that\n ITCH<\/jats:styled-content>\n targets\n TXNIP<\/jats:styled-content>\n for ubiquitin\u2010proteasome degradation in cardiomyocytes and ameliorates\n reactive oxygen species<\/jats:styled-content>\n \u2013induced cardiotoxicity through the thioredoxin system.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.115.002485","type":"journal-article","created":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T03:14:43Z","timestamp":1453432483000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["HECT\u2010Type Ubiquitin E3 Ligase ITCH Interacts With Thioredoxin\u2010Interacting Protein and Ameliorates Reactive Oxygen\u00a0Species\u2013Induced Cardiotoxicity"],"prefix":"10.1161","volume":"5","author":[{"given":"Yoichiro","family":"Otaki","sequence":"first","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsu","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Funayama","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata 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University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromasa","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Arimoto","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Shishido","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and 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