Zhishi xiebai guizhi decoction ameliorates mitochondrial dysfunction induced by myocardial ischemia-reperfusion injury in mice via the Autophagy-ACBP-TSPO axis

Abstract

Background Myocardial ischemia-reperfusion injury (MIRI) is often associated with oxidative stress, mitochondrial damage, programmed cell death, and autophagy. Protecting the mitochondrial function of myocardial tissue is critical for cardiac function. However, there is currently no effective treatment for MIRI. We aimed to determine whether zhishi xiebai guizhi decoction (ZXGD) attenuates MIRI through the autophagy-ACBP-TSPO axis. Methods A model of MIRI was established in mice by ligating the left anterior descending coronary artery for 30 min and reperfusion for 2 h. The myocardial injury was assessed by TTC-Evans blue and hematoxylin and eosin (HE) stains. The potential protein targets were identified using network analysis and molecular docking. Mitochondrial membrane potential and ATP production were detected using JC-1 assay and ATP assay kit, respectively. The target proteins were detected by western blotting, immunofluorescence analysis, and immunohistochemistry. Results ZXGD markedly attenuated myocardial damage, and enhanced cardiac function and mitochondrial morphology in mice accompanied with ischemia-reperfusion. It was found that AKT1-mTOR-mediated autophagy was possibly involved in the pretreatment of ZXGD on MIRI by network analysis and molecular docking. Experiments in vivo confirmed that ZXGD could inhibit myocardium autophagy, partly through activating the AKT1-mTOR signaling pathway. Furthermore, we revealed that ZXGD could promote ACBP expression and ACBP-TSPO binding in the myocardium, which might result from the regulation of autophagy. Conclusion ZXGD pretreatment significantly ameliorates MIRI by activating the autophagy-ACBP-TSPO axis in mice.