Evodiamine protects against cardiac remodeling in heart failure through modulation of calcium signaling and CD47.

Heart failure (HF) is characterized by pathological cardiac remodeling, leading to myocardial apoptosis, hypertrophy, and fibrosis. However, prognosis remains poor despite strides made in treatment regimens. Traditional Chinese Medicine (TCM) has been used to treat cardiovascular disorders, with evodiamine, an alkaloid derived from Tetradium ruticarpum, being identified for its cardioprotective effects. Although its potential to inhibit fibrosis and hypertrophy has been recognized, the underlying molecular mechanisms remain insufficiently understood. In this study, the cardioprotective effects of evodiamine were first evaluated in a transverse aortic constriction (TAC)-induced HF rat model and isoproterenol (ISO)-treated cardiomyocytes. Significant improvements in cardiac function and quantified reductions in apoptosis, hypertrophy, and fibrosis were observed following evodiamine treatment. Network pharmacology was subsequently applied to predict the molecular targets of evodiamine in HF, using data from the TCMSP and BATMAN-TCM databases and integrating differential gene expression analysis from an ISO-induced HF model (GSE225149). Gene enrichment and protein-protein interaction (PPI) network analyses highlighted key signaling pathways, including calcium signaling, and identified potential targets such as CD47. Experimental validation in both models confirmed that evodiamine modulated calcium signaling, specifically inhibiting CaMKII and RYR2 phosphorylation, and downregulated CD47 expression. Furthermore, CD47 overexpression attenuated evodiamine's protective effects and activated CaMKII, demonstrating a critical role for CD47, potentially through the CaMKII pathway, in mediating evodiamine's actions. These findings provide new insights into the cardioprotective mechanisms of evodiamine, highlighting its potential as a therapeutic agent for heart failure. Further molecular studies are recommended to fully identify its therapeutic benefits.