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Ezetimibe Protects Endothelial Cells against Oxidative Stress through Akt/GSK-3β Pathway

Current Medical Science 2018年第3期38卷 398-404页

作者： Jin QIN Li-li WANG Zhao-yu LIU Yuan-lin ZOU Yu-jie FEI Zheng-xiang LIU Department of Cardiology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China Department of Infection General Hospital of the Yangzte River Shipping Wuhan 430000 China Department of Gastroenterology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China 2

Ezetimibe was reported to pharmacologically defend against oxidative stress. This study was designed to investigate whether ezetimibe can protect against the oxidative stress induced by oxidized low-density lipoprotein （oxLDL） in vitro and the underlying mechanism. Human umbilical vein endothelial cells （HUVECs） were pretreated with ezetimibe and then exposed to oxLDL for 24 h. TUNEL assay and detection for the protein levels of cleaved caspase-3, Bcl-xl and Bcl-2 were employed to assess the oxLDL-induced endothelial apoptosis. Intracellular reactive oxygen species （ROS） generation was evaluated by measuring dichlorofluorescein （DCF） fluorescence. The activities of endothelial antioxidant enzymes [superoxide dismutase （SOD） and catalase] were tested via an enzymatic assay. The mitochondrial membrane potential （MMP） was monitored by flow cytometry using JC-I staining. Phosphorylation levels of glycogen synthase kinase-3β （p-GSK-3β） and Akt （p-Akt）, as well as total GSK-3β and Akt were determined by Western blotting. The results showed that ezetimibe treatment inhibited HUVECs apoptosis, intracellular ROS production, and enhanced antioxidant enzyme activities elicited by oxLDL. HUVECs exposed to oxLDL alone had reduced mitochondrial function, while ezetimibe pre-intervention could significantly rescue the MMP. Furthermore, the protein levels of p-GSK-3β and p-Akt in ezetimibe-pretreated HUVECs were markedly increased as compared with those in oxLDL-induced HUVECs. However, no significant effect on total GSK- 3β and Akt was found in ezetimibe-pretreated HUVECs. Taken together, it was concluded that ezetimibe protects against oxLDL-induced oxidative stress through restoring the MMP, which may be mediated by Akt-dependent GSK-3β phosphorylation.

关键词： ezetemibe oxidative stress mitochondrial dysfunction Akt/GSK-3β pathway

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