八味沉香丸激活磷脂酰肌醇3-激酶抑制铜死亡改善大鼠急性心肌缺血损伤OA

[Objective]To investigate the protective effect and underlying mechanisms of the Bawei Chenxiang Wan(BCW)against myocardial ischemic injury.[Methods]Myocardial ischemia in vivo was induced in rats by subcutaneous injection of isoproterenol(ISO),and ex vivo ischemia was established by coronary artery ligation in isolated rat hearts.The effects of BCW,alcohol extracts and its polar extracts were evaluated on ST segment on electrocardiogram(ECG),myocardial damage,hemodynamic parameters,and infarct size.The phosphorylation level of phosphatidylinositol 3-kinase(PI3K),the expression of cuproptosis-related proteins,and the content of Cu2+in myocardial tissue were detected.The regulatory relationship of the signaling pathway was verified using an oxygen-glucose deprivation(OGD)myocardial cell injury model,combined with PI3K agonists and inhibitors.[Results]BCW ameliorated ST-segment elevation on electrocardiograms(P<0.01),reduced serum levels of myocardial injury markers,improved hemodynamic parameters,upregulated PI3K phosphorylation(P<0.01),and decreased Cu2+accumulation in rats with myocardial ischemia(P<0.01).Moreover,BCW reduced the myocardial infarct size.In the isolated rat heart model of ischemia,both the ethanol extract and various solvent fractions of BCW exerted protective effects and reduced Cu2+content,among which the n-butanol fraction exhibited the most potent activity(P<0.01).Specifically,the n-butanol fraction upregulated PI3K phosphorylation(P<0.01)and downregulated the expression of cuproptosis-related proteins,including ferredoxin reductase 1(FDX1)(P<0.05),lipoic acid synthetase(LIAS),and dihydrolipoamide S-acetyltransferase(DLAT)oligomerization(P<0.05).In the OGD-induced cardiomyocyte injury model,treatment with a PI3K agonist inhibited DLAT oligomerization(P<0.05),whereas co-administration of a PI3K inhibitor attenuated the inhibitory effect of the n-butanol fraction on DLAT oligomer formation(P<0.05).[Conclusion]The n-butanol fraction of BCW exerts a significant protective effect against myocardial ischemic injury,and its mechanism may involve activation of the PI3K and inhibition of cuproptosis.