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Background  The  homologous to the E6‐AP carboxyl terminus (HECT) –type ubiquitin E3 ligase  ITCH  is an enzyme that plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin‐interacting protein ( TXNIP ) 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  ITCH  and its interaction with  TXNIP  to elucidate the mechanism of cardiotoxicity induced by  reactive oxygen species , such as doxorubicin and hydrogen peroxide.    Methods and Results  Protein interaction between  TXNIP  and  ITCH  in cardiomyocyte was confirmed by immunoprecipitation assays. Overexpression of  ITCH  increased proteasomal  TXNIP  degradation and augmented thioredoxin activity, leading to inhibition of  reactive oxygen species  generation, p38  MAPK , p53, and subsequent intrinsic pathway cardiomyocyte apoptosis in  reactive oxygen species –induced cardiotoxicity. Conversely, knockdown of  ITCH  using small interfering  RNA  inhibited  TXNIP  degradation and resulted in a subsequent increase in cardiomyocyte apoptosis. Next, we generated a transgenic mouse with cardiac‐specific overexpression of  ITCH , called the  ITCH ‐Tg mouse. The expression level of  TXNIP  in the myocardium in  ITCH ‐Tg mice was significantly lower than WT littermates. In  ITCH ‐Tg mice, cardiac dysfunction and remodeling were restored compared with WT littermates after doxorubicin injection and myocardial infarction surgery. Kaplan–Meier analysis revealed that  ITCH ‐Tg mice had a higher survival rate than WT littermates after doxorubicin injection and myocardial infarction surgery.    Conclusion  We demonstrated, for the first time, that  ITCH  targets  TXNIP  for ubiquitin‐proteasome degradation in cardiomyocytes and ameliorates  reactive oxygen species –induced cardiotoxicity through the thioredoxin system.

HECT ‐Type Ubiquitin E3 Ligase ITCH Interacts With Thioredoxin‐Interacting Protein and Ameliorates Reactive Oxygen Species–Induced Cardiotoxicity