Shenmai Injection Attenuates Pressure Overload-Induced Cardiac Hypertrophy by Modulating HRAS

Background/Objectives

Pressure overload-induced cardiac hypertrophy is a critical pathological precursor in the development of heart failure. Shenmai Injection (SMI) is widely used to treat cardiovascular diseases. However, its anti-hypertrophic effects and underlying molecular mechanisms remain insufficiently elucidated.

Materials and Methods

Network pharmacology, molecular docking, and experimental validation were systematically utilized. Firstly, active ingredients of SMI were screened using the SwissADME database, and their potential targets were predicted using SwissTargetPrediction. Hypertrophic Cardiomyopathy (HCM)-related targets were retrieved from the GeneCards, OMIM, and DrugBank databases. Protein-Protein Interaction (PPI) networks were optimized using CytoNCA and MCODE plugins, and binding affinities were validated via CB-DOCK. SMI's therapeutic efficacy was validated both in vitro and in vivo experiments.

Results

Network pharmacology analysis indicated that the active ingredients of SMI were predominantly enriched in the PI3K-Akt, MAPK, and Ras signaling pathways, with HRAS, SRC, and PRKCA identified as core targets. Molecular docking confirmed a high binding affinity between Methylophiopogonanone B and HRAS. Phalloidin staining demonstrated that SMI dose-dependently inhibited PE-induced hypertrophy in primary neonatal rat cardiomyocytes. TAC successfully induced cardiac hypertrophy in mice, evidenced by increased heart weight-to-body weight ratio, ventricular wall thickening (IVSd, LVPWd), elevated LVSP and LVEDP, and marked myocardial fibrosis. SMI intervention significantly ameliorated the hypertrophic phenotype, reversed hemodynamic parameters, mitigated fibrosis, and down-regulated the overexpressed HRAS.

Conclusions

SMI exerts anti-hypertrophic and anti-fibrotic effects by downregulating HRAS expression and subsequently inhibiting downstream hypertrophic signaling cascades, thereby effectively ameliorating pressure overload-induced ventricular remodeling.