miR-20a-5p inhibition attenuates post-myocardial infarction ventricular remodeling in association with mTORC1/S6 signaling

Background Maladaptive ventricular remodeling is the major pathological process linking myocardial infarction (MI) to heart failure, yet its upstream molecular drivers remain incompletely defined. Exosomal microRNAs (miRNAs) are emerging regulators of intercellular communication and cardiac pathology. This study sought to investigate the contribution of exosome-enriched miR-20a-5p in post-MI remodeling. Methods An acute myocardial infarction (MI) model was induced in SD rats through coronary ligation. Exosomes were isolated from infarcted and sham hearts, and expression of miR-20a-5p was quantified. Neonatal cardiomyocytes and fibroblasts were used for exosome uptake and functional assays. Functional enhancement and impairment assays with miR-20a-5p mimic/inhibitor, combined with rapamycin, were performed. Molecular mechanisms were assessed by RT-qPCR, Western blot, flow cytometry, and dual-luciferase reporter assays, while cardiac function and remodeling were evaluated by echocardiography and histology in vivo. Results Exosomal miR-20a-5p was significantly enriched after MI and preferentially internalized by cardiomyocytes and fibroblasts. Its upregulation promoted cardiomyocyte apoptosis, impaired autophagy, and induced fibroblast-to-myofibroblast transition via direct suppression of Ddit4 and activation of the mTORC1/S6 pathway. Inhibition of miR-20a-5p or mTORC1 partially reversed these effects, while combined therapy produced synergistic benefits, including reduced fibrosis, improved cardiomyocyte survival, and restored ventricular function in MI rats. Conclusions Exosomal miR-20a-5p drives adverse ventricular remodeling after MI through Ddit4-mediated mTORC1/S6 activation. Dual inhibition of miR-20a-5p and mTORC1 exerts synergistic cardioprotection, highlighting this axis as a promising target for preventing post-MI heart failure.