Hypoxic preconditioning attenuates angiotensin II and miR-6315-induced MAS1 inhibition to enhance myocardial survival

Background: The Angiotensin-(1–7)/MAS1 axis mediates cardioprotection, but its regulation under hypoxia, aging, and hypertension remains unclear. MicroRNAs (miRNAs) are key modulators of cardiovascular signaling, yet the role of miR-6315 in MAS1 regulation is unknown. Objective: To investigate how hypoxic preconditioning regulates the miR-6315–MAS1 axis and its role in cardiomyocyte survival under Angiotensin II (Ang II) stress and pathological conditions. Methods: Rat H9c2 and human AC16 cardiomyocytes were exposed to normoxia or hypoxia (0.5–24 h). MAS1 targeting by miR-6315 was validated using dual-luciferase assays. Gene and protein expression were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence. In vivo, Wistar–Kyoto and spontaneously hypertensive rats were subjected to graded hypoxia and aging models. Results: Hypoxic preconditioning induced transient MAS1 upregulation, with increased protein kinase B (AKT) activation and hypoxia-inducible factor-1 alpha (HIF1α) stabilization. miR-6315 directly suppressed MAS1, whereas its inhibition restored survival signaling. Ang II increased miR-6315 and apoptosis, effects attenuated by hypoxia. Aging and hypertension were associated with reduced MAS1 expression. Conclusion: Hypoxic preconditioning transiently relieves miR-6315-mediated repression of MAS1, activating a cardioprotective pathway that may represent a therapeutic target for enhancing myocardial resilience.