Lung‐Derived Small Extracellular Vesicles Containing miR‐15a‐5p/miR‐96‐5p Promote Myocardial Fibrosis in Hypertrophic Cardiomyopathy via Targeting SMAD7

Abstract 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 ( ^sEV miR‐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 ^sEV miR‐15a‐5p/96‐5p levels are elevated, predominantly originating from lung‐derived sEVs. GW4869‐mediated sEV suppression reduces pulmonary/cardiac ^sEV miR‐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 ^sEV miR‐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.