Fibroblast‐derived miR‐425‐5p alleviates cardiac remodelling in heart failure via inhibiting the TGF‐β1/Smad signalling

Abstract The pathological activation of cardiac fibroblasts (CFs) plays a crucial role in the development of pressure overload‐induced cardiac remodelling and subsequent heart failure (HF). Growing evidence demonstrates that multiple microRNAs (miRNAs) are abnormally expressed in the pathophysiologic process of cardiovascular diseases, with miR‐425 recently reported to be potentially involved in HF. In this study, we aimed to investigate the effects of fibroblast‐derived miR‐425‐5p in pressure overload‐induced HF and explore the underlying mechanisms. C57BL/6 mice were injected with a recombinant adeno‐associated virus specifically designed to overexpress miR‐425‐5p in CFs, followed by transverse aortic constriction (TAC) surgery. Neonatal mouse CFs (NMCFs) were transfected with miR‐425‐5p mimics and subsequently stimulated with angiotensin II (Ang II). We found that miR‐425‐5p levels were significantly downregulated in HF mice and Ang II‐treated NMCFs. Notably, fibroblast‐specific overexpression of miR‐425‐5p markedly inhibited the proliferation and differentiation of CFs, thereby alleviating myocardial fibrosis, cardiac hypertrophy and systolic dysfunction. Mechanistically, the cardioprotective actions of miR‐425‐5p may be achieved by targeting the TGF‐β1/Smad signalling. Interestingly, miR‐425‐5p mimics‐treated CFs could also indirectly affect cardiomyocyte hypertrophy in this course. Together, our findings suggest that fibroblast‐derived miR‐425‐5p mitigates TAC‐induced HF, highlighting miR‐425‐5p as a potential diagnostic and therapeutic target for treating HF patients.