Dipeptidyl peptidase 3 induces myocardial ischemia-reperfusion injury by mediating mitophagy and the intrinsic apoptotic pathway

Abstract

Background

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase that is regarded as a “myocardial inhibitor”. However, the role of DPP3 in myocardial ischemia-reperfusion injury (MIRI) remain to be investigated. The present study aimed to investigate the potential role of DPP3 in MIRI and elucidate the underlying mechanisms.

Methods

The AC16 cardiomyocyte cell line was used to investigate the interactions between DPP3 and its protein interactors, and assess its effects on the apoptosis of cardiomyocytes following oxygen glucose deprivation/reperfusion (OGD/R) treatment in vitro. An animal model of ischemia/reperfusion (I/R) injury was established using C57BL/6J mice for in vivo analyses. The role of DPP3 and the underlying mechanisms were investigated both in vitro and in vivo following DPP3 knockdown and overexpression.

Results

DPP3 interacted with Parkinson’s disease protein 7 (Park7), and DPP3 overexpression altered the expression levels of proteins related to the intrinsic apoptotic pathway and autophagy. This significantly downregulated the mitochondrial expression of cytochrome C, thereby exacerbating mitochondrial injury and increasing the rate of apoptosis following reperfusion. DPP3 knockdown reversed these effects; however, the simultaneous knockdown of DPP3 and Park7 did not confer the beneficial effects observed with DPP3 knockdown alone. DPP3 knockdown alleviated the extent of myocardial injury and improved cardiac function in the mouse model of I/R injury.

Conclusions

The study demonstrated that DPP3 mediates mitophagy and apoptosis in MIRI through its interaction with Park7. These findings have important implications, suggesting that targeting DPP3 and its associated signaling pathways may serve as a potential therapeutic strategy, and that the downregulation of DPP3 can potentially alleviate MIRI.