Madecassoside mitigates acute myocardial infarction injury by activating the PKCB/SPARC signaling pathway.

Abstract

The current treatments and drugs of myocardial infarction (MI) remain insufficient. In recent years, natural products have garnered significant attention for their potential in treating cardiovascular diseases due to their availability and lower toxicity. Saponins, in particular, showed promising effects for cardiac protection. In this study, we investigated the therapeutic effects of the saponin compound madecassoside in the treatment of MI, and underlying molecular mechanisms. The acute MI model was established in male mice by ligation of the left anterior descending coronary artery. The mice were treated with madecassoside (20 mg· kg^-1 ·d^-1, i.g.) for 14 days. After sacrificing the mice, hearts were harvested for analysis. We showed that madecassoside administration significantly mitigated cardiac function decline in MI mice by promoting angiogenesis and inhibiting myocardial cell apoptosis and fibrosis. By conducting systems pharmacology and RNA sequencing, we demonstrated that madecassoside upregulated SPARC gene expression by activating protein kinase C-β (PKCB) that had a strong promoting effect on endothelial cell angiogenesis, thus playing a crucial protective role against MI. We showed that inhibition of SPARC gene significantly reduced madecassoside-stimulated migration and tube formation of endothelial cells in vitro; co-administration of the PKCB-specific inhibitor ruboxistaurin (10 mg· kg^-1 ·d^-1, i.g.) abolished the cardioprotective effect of madecassoside in MI mice, validating the critical role of the PKCB/SPARC signaling pathway. This study demonstrates that madecassoside regulates the PKCB/SPARC pathway, promotes the proliferation and regeneration of vascular endothelial cells, and effectively alleviates the symptoms of MI.