Integrated Network Pharmacology and Experimental Validation Approach to Systematically Elucidate the Cardioprotective...

Core to advancing the study of traditional Chinese medicine (TCM) mechanisms is the integrated "computational prediction-experimental verification" strategy, which enables the precise identification of therapeutic targets through multilevel technological integration. Within this framework, this study systematically investigates the therapeutic mechanisms of Shengmai injection (SMI) against heart failure following myocardial infarction (MI). Initially, using network pharmacology approaches, we systematically screened TCMSP, BATMAN, and disease databases to identify 237 common targets of SMI and chronic heart failure. Through Cytoscape-based network topology analysis, we pinpointed 52 core targets, with KEGG pathway enrichment analysis revealing the PI3K-AKT signaling pathway as the crucial pathway. Subsequently, molecular docking technology demonstrated strong binding affinity (calculated affinity: -6.171 kcal/mol) between vitamin E (an active constituent by network pharmacology analysis) and the core target AKT1. At the experimental validation level, we established a mouse MI model by ligating the left anterior descending coronary artery, with continuous administration of SMI for 4 weeks. Experimental results showed that SMI significantly improved cardiac function of chronic heart failure, reduced myocardial fibrosis, inhibited cardiomyocyte apoptosis, and promoted macrophage polarization toward the reparative M2 phenotype. In the H9c2 cell model, SMI effectively improves mitochondrial function of cardiac cells induced by H₂O₂ and inhibits reactive oxygen species accumulation and mitochondrial membrane potential collapse. Mechanistic studies revealed that SMI regulates mitochondrial dysfunction by activating the AKT/Bcl-2 signaling axis, upregulating Bcl-2 expression, and inhibiting Bax. Through systematic methodological integration, this study not only elucidates the mechanism by which SMI inhibits mitochondrial dysfunction and macrophage polarization and attenuates ventricular remodeling through the AKT/Bcl-2 pathway but also provides a referential multidisciplinary research paradigm for investigating the mechanisms of TCM formulations.