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 (sEVAng-(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 sEVAng-(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 sEVAng-(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 sEVAng-(1-7) enhanced Akt2 phosphorylation, increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity, maintained calcium homeostasis, suppressed endoplasmic reticulum stress signaling (CHOP and p-JNK), and protected AC16 cells against H/R-induced apoptosis. sEVAng-(1-7) also attenuated oxidative stress under these conditions. Importantly, the protective effects of sEVAng-(1-7) remained after Mas receptor knockdown. Separately, Akt2 knockdown (Akt2KD) substantially weakened these benefits. These findings identify sEVAng-(1-7) as an promising therapeutic candidate, offering an effective, largely Mas-independent mechanism to combat MIRI with cardiomyocyte protection.