Small extracellular vesicles induced by Angiotensin-(1-7) enhance cardioprotection following myocardial ischemia-reperfusion injury

Although Angiotensin-(1-7) [Ang-(1-7)], a non-classical peptide of the renin-angiotensin system (RAS), is widely recognized for alleviating cardiovascular stress through activation of the Mas receptor. we identified a largely Mas receptor-independent pathway that expands its therapeutic potential in cardiac diseases. Our study demonstrated that Ang-(1-7) stimulated cardiomyocytes to release small extracellular vesicles (sEV Ang-(1-7) ), which exhibit enhanced cardioprotective effects compared with Ang-(1-7) administration alone. In both wild-type C57BL/6J mice and cardiac-specific Mas receptor knockout (cMas-KO) mice subjected to myocardial ischemia/reperfusion injury (MIRI), we found that enriched sEV Ang-(1-7) preserved cardiac function by attenuating cardiomyocyte apoptosis and oxidative stress following MIRI. These protective effects remained evident even when Mas receptor signaling was pharmacologically inhibited or genetically ablated. Moreover, in wild-type mice with MIRI, enriched sEV Ang-(1-7) provided significantly greater therapeutic efficacy in improving cardiac function than direct administration of Ang-(1-7). In AC16 human cardiomyocytes subjected to hypoxia/reoxygenation (H/R), enriched sEV Ang-(1-7) enhanced Akt2 phosphorylation, increased sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) activity, maintained calcium homeostasis, suppressed endoplasmic reticulum stress signaling (CHOP and p-JNK), and protected AC16 cells against H/R-induced apoptosis. sEV Ang-(1-7) also attenuated oxidative stress under these conditions. Importantly, the protective effects of sEV Ang-(1-7) remained after Mas receptor knockdown. Separately, Akt2 knockdown (Akt2KD) substantially weakened these benefits. These findings identify sEV Ang-(1-7) as an promising therapeutic candidate, offering an effective, largely Mas-independent mechanism to combat MIRI with cardiomyocyte protection.