miR-203 improves pressure overload-induced heart failure by targeting the IGFBP5/PI3K/AKT axis.

Heart failure (HF) represents the final stage of cardiovascular disease progression, characterized by high morbidity and mortality. Pressure overload in HF activates the PI3K/AKT pathway, and prolonged activation leads to pathological cardiac hypertrophy. However, the mechanism underlying sustained PI3K/AKT activation in pressure overload-induced HF remains unclear. In this study, we demonstrate that miR-203 overexpression in transgenic mice counteracts cardiac dysfunction and pathological remodeling in HF, whereas miR-203 downregulation exacerbates HF. At the cellular level, miR-203 overexpression significantly reduces Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and injury, while miR-203 knockdown aggravates these effects. Mechanistically, miR-203 binds to the 3' untranslated region (3'UTR) of insulin-like growth factor binding protein 5 (IGFBP5) mRNA, inhibiting IGFBP5 protein expression, thereby suppressing PI3K/AKT signaling and mitigating cardiomyocyte hypertrophy. Furthermore, we demonstrate that fibronectin-1 (FN1) is a critical functional partner for IGFBP5, as knockdown of FN1 attenuates IGFBP5-induced PI3K/AKT activation and hypertrophy. This study is the first to elucidate the role and mechanism of miR-203 in regulating pressure overload-induced HF, offering a potential genetic tool for HF therapy.