Optimizing myocardial cell protection with xanthine derivative KMUP‐3 potentiates autophagy through the PI3K/Akt/eNOS axis

Abstract Background Autophagy can have either beneficial or detrimental effects on various heart diseases. Pharmacological interventions improve cardiac function, which is correlated with enhanced autophagy. To assess whether a xanthine derivative (KMUP‐3) treatment coincides with enhanced autophagy while also providing cardio‐protection, we investigated the hypothesis that KMUP‐3 treatment activation of autophagy through PI3K/Akt/eNOS signalling offered cardioprotective properties. Methods The pro‐autophagic effect of KMUP‐3 was performed in a neonatal rat model targeting cardiac fibroblasts and cardiomyocytes, and by assessing the impact of KMUP‐3 treatment on cardiotoxicity, we used antimycin A‐induced cardiomyocytes. Results As determined by transmission electron microscopy observation, KMUP‐3 enhanced autophagosome formation in cardiac fibroblasts. Furthermore, KMUP‐3 significantly increased the expressions of autophagy‐related proteins, LC3 and Beclin‐1, both in a time‐ and dose‐dependent manner; moreover, the pro‐autophagy and nitric oxide enhancement effects of KMUP‐3 were abolished by inhibitors targeting eNOS and PI3K in cardiac fibroblasts and cardiomyocytes. Notably, KMUP‐3 ameliorated cytotoxic effects induced by antimycin A, demonstrating its protective autophagic response. Conclusion These findings enable the core pathway of PI3K/Akt/eNOS axis in KMUP‐3‐enhanced autophagy activation and suggest its principal role in safeguarding against cardiotoxicity.