PMID- 33495519 OWN - NLM STAT- MEDLINE DCOM- 20220125 LR - 20240226 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 42 IP - 10 DP - 2021 Oct TI - A GLP-1 analog lowers ER stress and enhances protein folding to ameliorate homocysteine-induced endothelial dysfunction. PG - 1598-1609 LID - 10.1038/s41401-020-00589-x [doi] AB - 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 eIF2alpha) 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 (ERO1alpha), 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 ERO1alpha mediated 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 ERO1alpha upregulation in endothelial cells and arteries. AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress. CI - (c) 2021. The Author(s), under exclusive licence to CPS and SIMM. FAU - Cheng, Chak Kwong AU - Cheng CK AD - School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China. AD - Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Luo, Jiang-Yun AU - Luo JY AD - School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China. AD - Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Lau, Chi Wai AU - Lau CW AD - School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China. AD - Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Cho, William Chi-Shing AU - Cho WC AD - Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China. FAU - Ng, Chi Fai AU - Ng CF AD - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Ma, Ronald Ching Wan AU - Ma RCW AD - 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. FAU - Tian, Xiao Yu AU - Tian XY AD - School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China. xytian@cuhk.edu.hk. AD - Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. xytian@cuhk.edu.hk. FAU - Huang, Yu AU - Huang Y AD - School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China. yu-huang@cuhk.edu.hk. AD - Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. yu-huang@cuhk.edu.hk. LA - eng PT - Journal Article DEP - 20210125 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Membrane Glycoproteins) RN - 0 (Molecular Chaperones) RN - 0 (Reactive Oxygen Species) RN - 0LVT1QZ0BA (Homocysteine) RN - 9P1872D4OL (Exenatide) RN - EC 1.- (ERO1A protein, human) RN - EC 1.- (Oxidoreductases) RN - EC 1.14.13.39 (NOS3 protein, human) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, mouse) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Animals MH - Endoplasmic Reticulum Stress/*drug effects MH - Endothelium, Vascular/*drug effects MH - Exenatide/*pharmacology MH - Homocysteine/*adverse effects MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Male MH - Membrane Glycoproteins/metabolism MH - Mice, Inbred C57BL MH - Molecular Chaperones/metabolism MH - Nitric Oxide Synthase Type III/metabolism MH - Oxidative Stress/drug effects MH - Oxidoreductases/metabolism MH - Protein Folding/*drug effects MH - Reactive Oxygen Species/metabolism MH - Mice PMC - PMC8463564 OTO - NOTNLM OT - AMPK OT - ER chaperone OT - ER stress OT - GLP-1 analog OT - endothelial dysfunction OT - exendin-4 OT - homocysteine OT - oxidative stress COIS- The authors declare no competing interests. EDAT- 2021/01/27 06:00 MHDA- 2022/01/27 06:00 PMCR- 2022/10/01 CRDT- 2021/01/26 05:44 PHST- 2020/08/04 00:00 [received] PHST- 2020/10/15 00:00 [accepted] PHST- 2021/01/27 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/01/26 05:44 [entrez] PHST- 2022/10/01 00:00 [pmc-release] AID - 10.1038/s41401-020-00589-x [pii] AID - 589 [pii] AID - 10.1038/s41401-020-00589-x [doi] PST - ppublish SO - Acta Pharmacol Sin. 2021 Oct;42(10):1598-1609. doi: 10.1038/s41401-020-00589-x. Epub 2021 Jan 25.