Angiotensin-(1-7) Alleviates Isoproterenol-Induced Cardiac Hypertrophy by Suppressing Autophagy and Apoptosis Through the Synergistic Action of Mas Receptor and Angiotensin II Type 2 Receptor.

AIM: The aim of this study is to determine whether Angiotensin-(1-7) [Ang-(1-7)] alleviates isoproterenol (ISO)-induced cardiac hypertrophy by suppressing excessive autophagy and apoptosis through coordinated Mas receptor (MasR) and angiotensin II type-2 receptor (AT(2)R) signaling, and to elucidate the underlying mechanisms. METHODS: ISO-induced hypertrophy was established in mice and assessed by echocardiography, histology, and hypertrophic markers. H9c2 cardiomyocytes were exposed to ISO and treated separately with A-779 (MasR antagonist), PD123319 (AT(2)R antagonist), and a combination of both receptor antagonists. Receptor interplay was examined using pharmacological blockade and co-immunoprecipitation. Autophagy and apoptosis were evaluated by transmission electron microscopy and TUNEL. RESULTS: Ang-(1-7) attenuated ventricular dysfunction, myocardial enlargement, and upregulation of hypertrophic markers in mice with ISO-induced hypertrophy. Pharmacological inhibition with A-779 and PD123319 revealed that Ang-(1-7) actions require reciprocal regulation between MasR and AT(2)R. Both receptors synergistically contributed to the anti-apoptotic effect, while the anti-autophagic response was mediated predominantly by MasR. Transmission electron microscopy and TUNEL staining confirmed that Ang-(1-7) treatment alleviated excessive autophagy and apoptosis in cardiomyocytes. Furthermore, experiments with dual receptor antagonists and co-immunoprecipitation showed an interaction between MasR and AT(2)R, supporting their coordinated signaling role in cardiac protection. CONCLUSION: Ang-(1-7) ameliorates ISO-induced cardiac hypertrophy by suppressing excessive autophagy and apoptosis via synergistic MasR-AT(2)R signaling. Receptor crosstalk may represent a therapeutic entry point for pathological hypertrophy.