Kukoamine A Activates Akt/GSK-3β Pathway to Repress Oxidative Stress and Inflammation to Alleviate Myocardial Ischemia-reperfusion Injury

Background Myocardial ischemia-reperfusion injury (MI/RI) is a serious complication after revascularization of myocardial infarction, which causes myocardium damage. Kukoamine A (KuA) can repress oxidative stress and neuronal apoptosis in cerebral ischemia animal models.Objective In the present study, our objective was to explore the role of KuA in MI/RI and the underlying mechanism of KuA in oxidative stress and inflammation of MI/RI.Methods H9c2 cells' cytotoxicity was detected using the lactate dehydrogenase (LDH) assay kit. ROS level was measured by immunofluorescence. Male C57BL/6 mice were used to establish MI/RI mice by ligating the left anterior descending coronary artery (LAD).Results KuA treatment decreased the apoptosis and the cytotoxicity, increased the viability, and reduced the activities of myocardial infarction markers (CKMB, MYO, and cTnI) in hypoxia/reoxygenation (H/R)-induced H9c2 cells. KuA reduced the levels of ROS, MDA, and inflammatory factors (IL-6, IL-1 beta, and TNF-alpha), and facilitated MMP and SOD levels in H/R-induced H9c2 cells. Besides, KuA activated Akt/GSK-3 beta axis, which was repressed by PI3K inhibitor LY294002. Moreover, KuA improved survival times, decreased the infarct size of mice, and recovered cardiac function in MI/RI mice. Finally, KuA alleviated MI/RI through Akt/GSK-3 beta pathway in vivo.Conclusion Thus, KuA exerts a protective function in MI/RI through the Akt/GSK-3 beta axis to repress oxidative stress and inflammation.