The impairment of autophagic flux has been widely recognized in myocardial ischemia-reperfusion (I/R) injury, but its underlying mechanism contributing to impaired autophagic flux is poorly understood. As celluar major degradation systems, autophagy and ubiquitin proteasome system (UPS) participate in the multitudinous progression of disease by interactive relationship. Especially UBE2D3, one of the ubiquitin-binding enzyme E2 family, is closely related to the regulation impairment of autophagic flux under I/R in our study. Therefore, this study aims to further explore the regulatory mechanism of UBE2D3 in I/R induced autophagy. We determined interference with UBE2D3 alleviated injury of myocardial cells both in vivo and in vitro. Conversely, when inhibiting proteasome function by injecting MG-132, myocardial infarct size of rats became increasingly enhanced, along with the high expression levels of LDH and CK-MB in serum, compared with myocardial I/R injury without treatment of MG-132. This had been caused by UBE2D3 promoting p62/SQSTM1(p62) ubiquitination(Ub), which lead to worsen the impairment of autophagic flux induced by myocardial I/R injury. In addition, UBE2D3 could also participate in the regulation of autophagy by negatively regulating mTOR. But more surprisingly, this mechanism was independent of the known mTOR-beclin1 pathway. These results suggested that in myocardial I/R injury, UBE2D3 promoted p62 ubiquitination to aggravate the impairment of autophagic flux. Moreover, mTOR was also involved in its regulation of autophagic flux in a way escaped from beclin1.
Keywords: Autophagy; Myocardial ischemia-reperfusion injury; UBE2D3; Ubiquitylation; p62/SQSTM1.
Copyright © 2021. Published by Elsevier Inc.