Lung-Derived Small Extracellular Vesicles Containing miR-15a-5p/miR-96-5p Promote Myocardial Fibrosis in Hypertrophic...

Small extracellular vesicles (sEVs) are membrane-bound nanoparticles released by cells for intercellular or inter-tissue communication and play key roles in multiple cardiovascular disorders. However, the mechanisms underlying sEV-mediated myocardial fibrosis in hypertrophic cardiomyopathy (HCM) are not well understood. In this study, it is discovered that the levels of miR-15a-5p and miR-96-5p in circulating sEVs (^sEVmiR-15a-5p/96-5p) are elevated in HCM patients with myocardial fibrosis. These sEVs enhance fibroblast proliferation and differentiation in vitro. Similar findings are observed in isopropanol (ISO)-induced myocardial fibrosis mouse model, where ^sEVmiR-15a-5p/96-5p levels are elevated, predominantly originating from lung-derived sEVs. GW4869-mediated sEV suppression reduces pulmonary/cardiac ^sEVmiR-15a-5p/96-5p levels, suggesting therapeutic potential. Importantly, the systemic trafficking of lung-derived sEVs is also mapped to cardiac tissue in vivo using a lung-specific lineage-tracing strategy using SFTPC (surfactant protein C) promoter-driven AAV9-CD63-GFP vectors. Administering lung-derived sEVs from ISO-treated mice into the myocardium increases cardiac fibroblast proliferation and scar formation. Furthermore, it is identified that miR-15a-5p and miR-96-5p directly target Smad7, reducing its expression, while SMAD7 overexpression reverses profibrotic effects. These findings indicate that lung-derived ^sEVmiR-15a-5p/96-5p may exacerbate myocardial fibrosis by targeting Smad7 in cardiac fibroblasts. Thus, lung-derived sEV miR-15a-5p and miR-96-5p can serve as novel biomarkers and therapeutic targets for managing HCM-related myocardial fibrosis.