Tongmai Yangxin pill mitigates myocardial ischemia/reperfusion injury by improving mitochondrial function and mitophagy: A potential role of estrogen receptor alpha and PTEN-induced putative kinase 1/Parkin pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial ischemia/reperfusion injury (MI/RI) is a common complication of acute myocardial infarction, with significant effects on clinical outcomes. Tongmai Yangxin pill (TMYX), a traditional Chinese medicine formula, is approved by the National Medical Products Administration (NMPA) for treating cardiovascular and cerebrovascular diseases. While empirical evidence supports its therapeutic efficacy for MI/RI, the underlying mechanisms remain incompletely understood. AIM OF THE STUDY: This study aimed to determine the effects of TMYX on mitophagy during MI/RI and explore its potential mechanisms. MATERIALS AND METHODS: A rat model of MI/RI and an H9c2 cell hypoxia/reoxygenation (H/R) model were established to evaluate the cardioprotective effects of TMYX. After identifying the drug components, serum and tissue samples post-administration, network pharmacology was combined with WGCNA to predict the mechanisms of TMYX in treating MI/RI. Additionally, gene silencing was employed to validate the mechanisms by which TMYX exerts its cardioprotective effects. RESULTS: TMYX treatment significantly reduced myocardial fibrosis and alleviated oxidative stress in MI/RI rats. A total of 148 compounds in TMYX were identified across different samples. Bioinformatics analysis identified estrogen receptor α (ERα) as a key factor in TMYX-mediated regulation of mitophagy. TMYX restored mitochondrial biogenesis and downregulated the genes associated with the PINK1/Parkin pathway. Silencing ERα in cardiomyocytes abolished the cardioprotective effects of TMYX. CONCLUSIONS: TMYX regulates the PINK1/Parkin signaling pathway via ERα activation, restores mitophagy balance, and protects against MI/RI-induced cardiac injury. This study identifies potential new therapeutic targets for TMYX in MI/RI treatment. However, given the complex multi-component composition of traditional Chinese medicine formulas, additional studies are necessary to confirm the findings of this research.