Xueshuantong injection alleviates ischemic heart failure via targeting PFKP-mediated endothelial-to-mesenchymal transition.

Abstract

BACKGROUND: Cardiac fibrotic remodeling is universally acknowledged as a hallmark of heart failure (HF) following acute ischemic events like myocardial infarction (MI), in which endothelial-to-mesenchymal transition (EndoMT) plays a pivotal role. Xueshuantong injection (XST), a standardized preparation enriched in Panax notoginseng saponins, has been widely used in cardiovascular diseases, yet its effects on post-MI HF and EndoMT-related cardiac fibrosis remain unknown. PURPOSE: This study aimed to investigate whether XST alleviates post-MI HF by inhibiting EndoMT, and to elucidate its underlying molecular mechanisms via thermal proteome profiling (TPP) assay. METHODS: A post-MI HF model was induced by left anterior descending coronary artery ligation in mice, and hypoxia-stimulated human umbilical vein endothelial cells (HUVECs) were used for in vitro validation. Cardiac function and fibrosis were assessed by echocardiography, Masson staining, and flow cytometry. The potential molecular target of XST was explored using TPP coupled with mass spectrometry, immunohistochemistry, and immunofluorescence. RESULTS: XST treatment significantly improved cardiac contractile function, reduced HF biomarker levels, and prevented cardiac morphological changes in MI-induced HF mice. Histological analysis demonstrated that XST mitigated cardiac fibrosis by suppressing EndoMT. In vitro, XST prevented hypoxia-induced EndoMT and preserved endothelial function. Mechanistically, TPP assay identified platelet type phosphofructokinase (PFKP) as a molecular target of XST. PFKP overexpression promoted EndoMT. XST suppressed PFKP activity and glycolysis in endothelial cells, thereby inhibiting EndoMT, finally exerting cardioprotective and anti-fibrotic effects. CONCLUSION: These findings reveal a previously unrecognized therapeutic role of XST in the treatment of post-MI HF by attenuating EndoMT-driven cardiac fibrosis, via targeting the PFKP-glycolysis axis.