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.
Highlights
A wealth of evidence suggests that the renin–angiotensin system (RAS) plays an important role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury (Mann et al, 2015; Donnarumma et al, 2016)
Our results demonstrated that plasma level and activity of PRCP and the levels of Ang-(1–7) and BK-(1–9) were increased in patients with ST-segment–elevated acute myocardial infarction (AMI) and primary percutaneous coronary intervention (PCI), as compared with healthy participants and those with unstable angina, suggesting that the PRCP–Ang-(1–7)/BK-(1–9) axis might be involved in the pathogenesis of myocardial I/R injury
PRCP protected against rat myocardial I/R injury via a paradoxical regulation of cardiomyocyte mitophagy during ischemia and reperfusion phases, which was mediated by downstream Ang-(1–7) and BK-(1–9) upregulation (Figure 6)
Summary
A wealth of evidence suggests that the renin–angiotensin system (RAS) plays an important role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury (Mann et al, 2015; Donnarumma et al, 2016). Angiotensin II (Ang II) is upregulated after myocardial I/R and aggravates myocardial injury mediated by Ang II type 1 (AT1) receptor (Mann et al, 2015). Treatment with angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor blockers improves I/R injury (Donnarumma et al, 2016). We found that ACE2, a zinc metalloproteinase, and its catalytic product angiotensin-(1– 7) [Ang-(1–7)] provided significant cardioprotection, the exact mechanisms are not elaborated (Dong et al, 2012; Hao P. et al, 2015). The RAS may have beneficial effects against acute myocardial infarction (AMI) by maintaining the balance between the deleterious ACE– Ang II–AT1 receptor axis and the beneficial ACE2–Ang-(1–7)– Mas receptor axis
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