miR‐199a‐3p mitigates simulated microgravity‐induced cardiac remodeling by targeting MEF2C

Abstract Microgravity‐induced cardiac remodeling and dysfunction present significant challenges to long‐term spaceflight, highlighting the urgent need to elucidate the underlying molecular mechanisms and develop precise countermeasures. Previous studies have outlined the important role of miRNAs in cardiovascular disease progression, with miR‐199a‐3p playing a crucial role in myocardial injury repair and the maintenance of cardiac function. However, the specific role and expression pattern of miR‐199a‐3p in microgravity‐induced cardiac remodeling remain unclear. We separately utilized mouse tail suspension and rhesus monkey bedrest models to construct simulated microgravity conditions and observed significant cardiac remodeling and dysfunction in both species, accompanied by a marked downregulation of miR‐199a‐3p expression in their hearts. By generating cardiac‐specific transgenic (TG) mice and subjecting them to tail suspension, we observed that the wild‐type (WT) mice exhibited cardiac remodeling characterized by increased fibrosis, smaller cardiomyocytes, and reduced ejection fraction (EF). In contrast, the miR‐199a‐3p TG mice were able to counteract the cardiac remodeling induced by tail suspension, demonstrating that miR‐199a‐3p can protect against simulated microgravity‐induced cardiac remodeling. Subsequently, we employed an AAV9‐mediated delivery system for cardiac‐specific overexpression of miR‐199a‐3p, significantly mitigating cardiac remodeling and dysfunction induced by simulated microgravity. Mechanistically, miR‐199a‐3p targets MEF2C, inhibiting its activation induced by simulated microgravity, thereby suppressing the associated cardiac remodeling. This research identifies miR‐199a‐3p as a promising therapeutic target with significant potential for precise protection against spaceflight‐induced cardiovascular dysfunction.