Bushen Huoxue Yiqi formula alleviates cardiac fibrosis in ischemic heart failure through SIRT1/Notch1 pathway-mediated EndMT

BACKGROUND: Cardiac fibrosis plays a crucial role in the development of heart failure (HF) following myocardial infarction (MI). Endothelial-mesenchymal transition (EndMT) is one of the key drivers of cardiac fibrosis and subsequent cardiac dysfunction. The traditional Chinese medicine formula Bushen Huoxue Yiqi Formula (BHYF) is an effective prescription for treating HF, significantly improving cardiac function in patients. However, the underlying mechanisms of BHYF's efficacy remain inadequately understood. OBJECTIVE: This study aims to determine whether BHYF ameliorates HF by inhibiting cardiac fibrosis and to elucidate the intrinsic mechanisms involved. METHODS: A post-MI HF model was established by ligating the left anterior descending coronary artery in rats, and human umbilical vein endothelial cells (HUVEC) were stimulated with hypoxia/reoxygenation (H/R) in vitro. Active compounds in BHYF were identified using HPLC. Cardiac function and morphology were assessed using echocardiography, TTC staining, HE staining, Masson's trichrome, and Sirius Red staining. The mechanism of action of BHYF was evaluated using Western blotting, immunohistochemistry, and immunofluorescence. RESULTS: A total of 98 compounds, including glycosides, phenolic compounds, carboxylic acids, and others, were identified or preliminarily identified. BHYF improved cardiac function and myocardial damage in rats with MI-induced HF and mitigated cardiac fibrosis by inhibiting EndMT. Mechanistically, BHYF treatment inhibited EndMT by modulating the SIRT1/Notch1 pathway, thereby exerting anti-fibrotic effects in the heart. CONCLUSION: Targeting EndMT based on the SIRT1/Notch1 pathway, BHYF may represent a novel antifibrotic therapeutic strategy, providing a scientific basis for the development of new cardiovascular drugs.