piR-45962 exacerbates autophagic apoptosis in aged myocardial ischemia-reperfusion injury through modulation of the HNRNPH1/GATA5 signaling axis.

Abstract

Myocardial ischemia-reperfusion (I/R) injury is a significant contributor to poor prognosis after myocardial infarction, and the degree of irreversible myocardial damage is closely related to age. In I/R injury, ischemic and hypoxic stress triggers the coordinated activation of apoptosis and autophagy in cardiomyocytes. Although Piwi-interacting RNAs (piRNAs) have been implicated in the regulation of both apoptosis and autophagy, their specific roles and particularly their functional integration in governing this dual cell death response during I/R injury remain poorly understood. Using left anterior descending coronary artery ligation in an aging rat model and a D-galactose-induced rat cardiomyocyte line to construct an aging cardiomyocyte model, we investigate the cell apoptosis and autophagy following reperfusion injury both in vitro and in vivo. The present study focuses on the upregulation of piR-45962 in reperfusion injury in vitro and in vivo, and the indicators of apoptosis and autophagy are significantly different. Mechanistic research of piR-45962 shows that heterogeneous nuclear ribonucleoprotein 1 (HNRNPH1) is a target protein for piR-45962, and as an RNA-binding protein implicated in apoptotic regulation, HNRNPH1 could interact with GATA binding protein 5 (GATA5) to exacerbate autophagic apoptosis. Together, our results reveal the mechanism by which piR-45962 downregulates GATA5 expression through upregulation of HNRNPH1, thereby establishing a novel piR-45962-HNRNPH1-GATA5 regulatory axis that contributes to aged myocardial injury during I/R.