A GLP-1 analog lowers ER stress and enhances protein folding to ameliorate homocysteine-induced endothelial dysfunction  

作　　者：Chak Kwong Cheng Jiang-Yun Luo Chi Wai Lau William Chi-shing Cho Chi Fai Ng Ronald Ching Wan Ma Xiao Yu Tian Yu Huang 

机构地区：[1]School of Biomedical Sciences and Li Ka Shing Institute of Health Science,The Chinese University of Hong Kong,Hong Kong SAR,China [2]Heart and Vascular Institute and Shenzhen Research Institute,The Chinese University of Hong Kong,Hong Kong SAR,China [3]Department of Clinical Oncology,Queen Elizabeth Hospital,Kowloon,Hong Kong SAR,China [4]Department of Surgery,The Chinese University of Hong Kong,Hong Kong SAR,China [5]Department of Medicine and Therapeutics,Hong Kong Institute of Diabetes and Obesity,and The Li Ka Shing Institute of Health Sciences,The Chinese University of Hong Kong,Hong Kong SAR,China

出　　处：《Acta Pharmacologica Sinica》2021年第10期1598-1609,共12页中国药理学报（英文版）

基　　金：This work was supported by Health and Medical Research Fund[Grant numbers 05162906 and 05161746];Early Career Scheme[Grant number 24122318];the National Natural Science Foundation of China[Grant numbers 91739103 and 91939302];Hong Kong Research Grants Council[Grant numbers 14112919 and C4024-16W].

摘　　要：Hyperhomocysteinemia(HHcy)is an independent risk factor for cardiovascular diseases and increases mortality in type 2 diabetic patients.HHcy induces endoplasmic reticulum(ER)stress and oxidative stress to impair endothelial function.The glucagon-like peptide 1(GLP-1)analog exendin-4 attenuates endothelial ER stress,but the detailed vasoprotective mechanism remains elusive.The present study investigated the beneficial effects of exendin-4 against HHcy-induced endothelial dysfunction.Exendin-4 pretreatment reversed homocysteine-induced impairment of endothelium-dependent relaxations in C57BL/6 mouse aortae ex vivo.Four weeks subcutaneous injection of exendin-4 restored the impaired endothelial function in both aortae and mesenteric arteries isolated from mice with diet-induced HHcy.Exendin-4 treatment lowered superoxide anion accumulation in the mouse aortae both ex vivo and in vivo.Exendin-4 decreased the expression of ER stress markers(e.g.,ATF4,spliced XBP1,and phosphorylated eIF2α)in human umbilical vein endothelial cells(HUVECs),and this change was reversed by cotreatment with compound C(CC)(AMPK inhibitor).Exendin-4 induced phosphorylation of AMPK and endothelial nitric oxide synthase in HUVECs and arteries.Exendin-4 increased the expression of endoplasmic reticulum oxidoreductase(ERO1α),an important ER chaperone in endothelial cells,and this effect was mediated by AMPK activation.Experiments using siRNA-mediated knockdown or adenoviral overexpression revealed that ERO1αmediated the inhibitory effects of exendin-4 on ER stress and superoxide anion production,thus ameliorating HHcy-induced endothelial dysfunction.The present results demonstrate that exendin-4 reduces HHcy-induced ER stress and improves endothelial function through AMPK-dependent ERO1αupregulation in endothelial cells and arteries.AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress.

关 键 词：HOMOCYSTEINE GLP-1 analog EXENDIN-4 AMPK ER stress ER chaperone oxidative stress endothelial dysfunction 

分 类 号：R96[医药卫生—药理学]