AUTHOR=Hao Panpan , Liu Yanping , Guo Haipeng , Zhang Zhongwen , Chen Qingjie , Hao Guoxiang , Zhang Cheng , Zhang Yun TITLE=Prolylcarboxypeptidase Mitigates Myocardial Ischemia/Reperfusion Injury by Stabilizing Mitophagy JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=8 YEAR=2020 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.584933 DOI=10.3389/fcell.2020.584933 ISSN=2296-634X ABSTRACT=

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.