Soluble receptor for advance glycation end-products inhibits ischemia/reperfusion-induced myocardial autophagy via the STAT3 pathway

The pathogenesis of myocardial ischemia/reperfusion (I/R) is poorly understood, but recent evidence suggests that autophagy plays crucial roles in I/R injuries. Soluble receptor for advanced glycation end-products (sRAGE) exerts protective effects during I/R by decreasing cardiac apoptosis, which is mediated via increasing the ubiquitin proteasome system (UPS) and signal transducer and activator of transcription 3 (STAT3). The present study examined the effects and mechanisms of sRAGE on I/R-triggered cardiac autophagy. I/R was performed in mice or primary neonatal cardiomyocytes with or without sRAGE administration or overexpression. Cardiac function and infarct size were detected in mouse hearts. Apoptosis, autophagy and autophagy-related signaling pathways were detected in mouse hearts and cardiomyocytes. The results demonstrated that sRAGE significantly improved cardiac function and reduced infarct size during I/R in mice. sRAGE inhibited I/R-induced apoptosis, which correlated with a reduction in autophagy-associated proteins, including ATG7, Beclin-1 and microtubule-associated protein 1 light chain 3 (LC3). sRAGE reduced autophagosome formation during I/R in vivo and in vitro. sRAGE significantly activated STAT3, but not mammalian target of rapamycin (mTOR), during I/R in vivo and in vitro, and suppression of STAT3 abolished the sRAGE inhibition of autophagy during I/R in vitro. Activation of autophagy using ATG7 overexpression with an adenovirus significantly abolished the sRAGE-induced reduction of cardiac apoptosis during I/R. These results suggest that sRAGE inhibits I/R injuries in the heart via a decrease in autophagy, a process that is dependent on STAT3 activation. [Display omitted] •It was reported sRAGE inhibited autophagy during I/R for the first time.•sRAGE inhibited I/R-triggered autophagy via an mTOR-independent pathway.•The protecting effect of sRAGE was dependent on inhibition of autophagy during I/R.