Septin4 Aggravates Hypoxia-Induced Cardiomyocytes Injury by Promoting HIF-1α Ubiquitination and Degradation through VHL

Abstract Backgrounds: Myocardial ischemia, characterized by insufficient nutrients and oxygen supply, is the most common cause of ischemic heart disease. Hypoxia-induced cardiomyocytes injury is the pathogenic feature of myocardial ischemia. Although previous studies have reported that the proapoptotic protein Septin4 contributes to prevent some cancers by promoting tumor cells apoptosis mainly through X-linked inhibitors of apoptosis (XIAPs), little is known its role in hypoxia-induced cardiomyocytes injury and its other new interacting partner. Results: In the current study, Septin4 is found to be involved in cardiomyocytes injury to hypoxia. The overexpression of Septin4 significantly aggravated hypoxic cardiomyocytes apoptosis assessed by cell viability assay and flow cytometry analysis. Mechanistically, hypoxia-inducible factor 1 alpha (HIF-1α) is confirmed as a novel protein mainly binding with GTPase domain of Septin4 by co-immunoprecipitation. Additionally, we found that the protective factor HIF-1α is down-regulated by Septin4 and the underlying mechanism is the von Hippel-Lindau protein (VHL)-mediated ubiquitin-proteasome degradation. Conclusions: These findings suggest that Septin4 aggravates hypoxia-induced cardiomyocytes injury by promoting HIF-1α ubiquitination and degradation by targeting to VHL, which may be beneficial to provide effective strategies for clinical treatment of myocardial ischemia and ischemic heart disease.