Integrating transcriptomics and network pharmacology to investigate YangxinDingji Capsule alleviates myocardial injury in tachyarrhythmia rat.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Tachyarrhythmia is a key risk factor for sudden cardiac death. YangxinDingji Capsule (YXDJ) has shown promising cardioprotection effects in treating arrhythmias, but its mechanism of action remains unclear. AIM OF THE STUDY: To investigate the therapeutic mechanism of YXDJ in treating myocardial injury caused by tachyarrhythmias, integrating network pharmacology and transcriptomics. MATERIALS AND METHODS: The cardioprotective effects of YXDJ were evaluated in a rat model of tachyarrhythmia induced by isoproterenol (ISO). The chemical components of YXDJ were identified using Ultra Performance Liquid Chromatography-Quadrupole-Exactive Orbitrap-High Resolution Mass Spectrometry (UPLC-Q-Exactive-Orbitrap HRMS). Network pharmacology integrated with transcriptomics was used to predict potential biological targets and pathways. Results were validated using RT-qPCR, immunofluorescence (IF), and Western blot (WB). RESULTS: YXDJ significantly reduced electrocardiogram (ECG) arrhythmias, improved myocardial injury pathology, decreased cardiac index and injury area, and alleviated cardiac dysfunction. Additionally, YXDJ reduced the expression levels of cardiac troponin T2 (TNNT2) and high-sensitivity cardiac troponin (hs-cTn) improved cardiac ultrastructure, and mitigated inflammatory responses. A total of 122 chemical constituents in YXDJ were identified using UPLC-Q-Exactive-Orbitrap HRMS. Network pharmacology analysis further identified 19 active components and 360 potential targets associated with YXDJ. Transcriptomic analysis indicated that the Actin Alpha Cardiac Muscle 1 (ACTC1) and the cAMP/PKA pathway as key targets and signaling pathways in isoproterenol-induced myocardial injury with tachycardia. In vivo experiments demonstrated that YXDJ significantly suppressed the cAMP/PKA/ACTC1 pathway expression in rats with tachyarrhythmias. RT-qPCR and WB analyses further confirmed that YXDJ treatment inhibited the expression of cAMP, PKA and ACTC1. CONCLUSION: YXDJ ameliorates myocardial injury in tachyarrhythmia by inhibiting cAMP/PKA/ACTC1 expression. The findings of this study are based on a single batch of YXDJ capsules and therefore have certain limitations.