Prolylcarboxypeptidase Mitigates Myocardial Ischemia/Reperfusion Injury by Stabilizing Mitophagy

The role of prolylcarboxypeptidase (PRCP) in myocardial ischemia/reperfusion (I/R) injury is unclear. Herein, we aimed to evaluate the protective effect of the PRCP-angiotensin-(1-7) [Ang-(1-7)]/bradykinin-(1-9) [BK-(1-9)] axis on myocardial I/R injury and identify the mechanisms involved. Plasma PRCP level and activity, as well as Ang-(1-7) and BK-(1-9) levels, were compared in healthy subjects, patients with unstable angina, and those with ST-segment-elevated acute myocardial infarction (AMI). Thereafter, the effects of PRCP overexpression and knockdown on left ventricular function, mitophagy, and levels of Ang-(1-7) and BK-(1-9) were examined in rats during myocardial I/R. Finally, the effects of Ang-(1-7) and BK-(1-9) on I/R-induced mitophagy and the signaling pathways involved were investigated in vitro in rat cardiomyocytes. AMI patients showed increased plasma level and activity of PRCP and levels of Ang-(1-7) and BK-(1-9) as compared with healthy subjects and those with unstable angina. PRCP protected against myocardial I/R injury in rats by paradoxical regulation of cardiomyocyte mitophagy during the ischemia and reperfusion phases, which was mediated by downstream Ang-(1-7) and BK-(1-9). We further depicted a possible role of activation of AMPK in mitophagy induction during ischemia and activation of Akt in mitophagy inhibition during reperfusion in the beneficial effects of Ang-(1-7) and BK-(1-9). Thus, the PRCP-Ang-(1-7)/BK-(1-9) axis may protect against myocardial I/R injury by paradoxical regulation of cardiomyocyte mitophagy during ischemia and reperfusion phases.