Abstract 13484: The HECT Type E3 Ligase ITCH Ameliorates Left Ventricular Remodeling and Mortality after Myocardial Infarction
Background: Oxidative stress and subsequent cardiomyocyte apoptosis are relavant factors myocardial remodeling in myocardial infarction. HECT-type ubiquitin E3 ligase ITCH is an enzyme which plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin-interacting protein (TXNIP) is a negative regulator of thioredoxin system, scavenging reactive oxygen species (ROS). In the present study, we examined whether ubiquitin E3 ligase ITCH attenuates myocardial infarction through ubiquitin proteasomal TXNIP degradation.
Methods and Results: We confirmed protein interaction between TXNIP and ITCH in cardiomyocytes by immunoprecipitation. Overexpression of ITCH increased proteasomal TXNIP degradation and augmented thioredoxin activity, which led to inhibition of ROS generation, p38 mitogen-activated protein kinase, p53, and subsequent intrinsic cardiomyocyte apoptosis after hydrogen peroxide stimulation. Conversely, siRNA-mediated inhibition of ITCH inhibited TXNIP degradation and subsequently increased in cardiomyocyte apoptosis. Next, we generated transgenic mice for cardiac-specific overexpression of ITCH (ITCH-Tg mice). The myocardial TXNIP expression was significantly lower in ITCH-Tg mice than in wild type littermates. ITCH-Tg mice ameliorated cardiac dysfunction and left ventricular remodeling after myocardial infarction. Kaplan-Meier analysis revealed that ITCH-Tg mice had higher survival rate than wild type littermates after myocardial infarction.
Conclusion: We demonstrated for the first time that ITCH inhibits oxidative stress and subsequent apoptosis through inhibition of TXNIP, p38, p53, and intrinsic apoptosis pathway in cardiomyocytes and attenuates cardiac remodeling after myocardial infarction.
Author Disclosures: O. Yoichiro: None. T. Watanabe: None. H. Takahashi: None. T. Narumi: None. S. Kadowaki: None. Y. Honda: None. T. Arimoto: None. T. Shishido: None. T. Miyamoto: None. I. Kubota: None.
- © 2014 by American Heart Association, Inc.