14-3-3/HIP-55 complex attenuates cardiomyocyte apoptosis

Abstract

Myocardial infarction (MI), a leading cause of death worldwide, results in cardiac damage mainly due to cardiomyocyte death. Early endogenous protection against cardiomyocyte death is crucial to limit infarct size and improve clinical outcomes. Previous studies have shown that 14-3-3 proteins play a vital role in cardiomyocyte survival. However, the fundamental mechanism remains unclear. Here, we revealed that 14-3-3 recruited HIP-55 forming a complex to suppress MI-induced cardiomyocyte death in response to myocardial infarction injury. The 14-3-3 partner protein-HIP-55 confers protection against MI-induced cardiomyocyte apoptosis. Mechanistically, the kinase RSK1 phosphorylates HIP-55 S269/T291 sites to promote the 14-3-3/HIP-55 complex formation which suppresses the ASK1 apoptotic pathway. Consistent with this mechanism, S269A/T291A-mutated HIP-55, which is defective in RSK1 phosphorylation and 14-3-3/HIP-55 complex formation, failed to protect against MI-induced cardiomyocyte apoptosis in vivo and in vitro. In summary, these findings demonstrate that the 14-3-3/HIP-55 complex plays a key role in cardiomyocyte survival. Targeting 14-3-3/HIP-55 may be a new therapeutic approach in the setting of acute myocardial damage.