Suxiao Jiuxin Pills Attenuate Myocardial Ischemia Injury through Multi-Component Synergy and Ligustilide-Mediated AKT/GSK3β/HIF-1α Pathway Activation

Abstract Myocardial infarction (MI), resulting from acute occlusion of the coronary artery, induces myocardial ischemia, hypoxia, and necrosis, and remains a leading cause of morbidity and mortality worldwide. Suxiao Jiuxin Pills (SJP), a widely used proprietary Chinese medicine for coronary heart disease and angina pectoris, have yet to be fully elucidated regarding their cardioprotective efficacy and underlying mechanisms against AMI. In the present study, an AMI mouse model was generated via permanent ligation of the left anterior descending (LAD) artery. Mice were randomly assigned to five groups: sham-operated, model, low-dose SJP (78 mg/kg), high-dose SJP (156 mg/kg), and captopril (positive control). Following 7 consecutive days of intragastric gavage, cardiac function, serum biomarkers of myocardial injury, and infarct size were systematically evaluated. Concurrently, an oxygen‑glucose deprivation (OGD) model was established in H9c2 cardiomyocytes to investigate the protective actions of four major SJP constituents—borneol(BOR), ferulic acid(FA), ligustilide (LIG), and senkyunolide A(SEA). In vivo, SJP treatment significantly preserved cardiac performance, diminished circulating levels of Creatine kinase MB (CK-MB), cardiac troponin T (cTnT), and Lactate dehydrogenase (LDH), attenuated histopathological damage and interstitial fibrosis, and markedly reduced the extent of myocardial infarction. In vitro, all four compounds concentration‑dependently improved cell survival and counteracted oxidative injury. Mechanistic exploration revealed that LIG, in particular, preserved mitochondrial membrane potential through activation of the AKT/GSK3β signaling cascade, concomitant with suppression of HIF‑1α overexpression. Collectively, these findings demonstrate that SJP confers substantial protection against ischemic/hypoxic myocardial injury, an effect attributable, at least in part, to LIG‑mediated regulation of the AKT/GSK3β/HIF‑1α axis and the consequent stabilization of mitochondrial homeostasis.