Cardio-protective effects of angiotensin-(1-5) via mas receptor in rats against ischemic-perfusion injury

Abstract

Angiotensin-(1-5) [Ang-(1-5)], which is a metabolite of Ang-(1-7) catalyzed by angiotensin-converting enzyme, is a novel pentapeptide of the renin-angiotensin system. Ang-(1-7), Ang III and Ang IV have a cardio-protective effect via Mas receptor, Ang II type 2 receptor (AT2R) and AT4R, respectively. However, it is not clear whether Ang-(1-5) has cardio-protective effects. The aim of this study is to investigate whether Ang-(1-5) protects the heart against ischemia-reperfusion (I/R) injury. After sacrificing Sprague-Dawley rats, the hearts were perfused with Krebs-Henseleit buffer for a 20 min pre-ischemic period with and without Ang-(1-5) followed by 20 min global ischemia and 50 min reperfusion. Ang-(1-5) (1 μM) improved changes in post-ischemic left ventricular developed pressure (LVDP), ±dP/dt, and post-ischemic left ventricular end-diastolic pressure (LVEDP) induced by reperfusion compared to control hearts. Ang-(1-5) decreased myocardial infarct size and LDH activity, and increased coronary flow and the amount of atrial natriuretic peptide (ANP) in coronary effluent during reperfusion compared to control hearts. Pretreatment with Mas receptor antagonist but not with AT1R or AT2R antagonist attenuated the improvement of changes in I/R-induced ventricular hemodynamics by Ang-(1-5). Ang-(1-5) treatment decreased Bax, caspase-3 and caspase-9 protein levels, and increased Bcl-2 protein level, which were attenuated by A779 pretreatment. Ang-(1-5) treatment increased Mn-superoxide dismutase, catalase, and heme oxygenase-1 protein levels, which was attenuated by A779 pretreatment. These results suggest that the cardio-protective effects of Ang-(1-5) against I/R injury may be partly related to activating anti-oxidant and anti-apoptotic enzymes via Mas receptor.