PMID- 27133040 OWN - NLM STAT- MEDLINE DCOM- 20170131 LR - 20211203 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 80 DP - 2016 May TI - Alpha-lipoic acid defends homocysteine-induced endoplasmic reticulum and oxidative stress in HAECs. PG - 63-72 LID - S0753-3322(15)30529-1 [pii] LID - 10.1016/j.biopha.2016.02.022 [doi] AB - BACKGROUND: Oxidative stress and endoplasmic reticulum (ER) stress play vital roles in the development of atherosclerosis. And hyperhomocysteinemia (HHCY) has been recognized as an independent risk factor for this process. Alpha-lipoic acid, a disulphide-containing compound, can scavenge reactive oxygen species, inhibit the formation of free radicals and chelate metal to maintain the homeostasis in the cells. This study aimed to determine the protecting effects of Alpha-lipoic acid (ALA) on homocysteine (HCY) induced injuries to human aortic endothelial cells (HAECs) and uncover the underlying mechanisms. METHODS: HAECs were treated with ALA in the presence/absence of HCY. The mechanism of ALA against HCY-induced cell injury was evaluated using Western blotting, real-time RT-PCR. Reactive oxygen Species (ROS) was detected by flow cytometry analysis. Mitochondrial membrane potential in HCY-treated HAECs was measured by Rhodamine 123 staining, and the samples were observed by confocal laser scanning microscopy. RESULTS: ALA suppressed the HCY-stimulated ROS generation, as well as the NF-kappaB transcriptional activation, and ICAM-1, VCAM-1 expression. ALA also elevated the bcl-2 and reduced caspase3, 9 expressions in the HCY- induced HAECs. Simultaneously, ALA could inhibit activation of ER stress-associated sensors GRP78, IRE1alpha, ATF6, P-PERK, P-eIF2alpha, CHOP and ATF4 induced by HCY. In addition, using GSH inhibitor, we proved ALA reduced the expressions of GRP78, ATF4 and IRE1alpha by generating GSH. CONCLUSIONS: ALA ameliorated HCY-induced ER stress and oxidation then reduced cells apoptosis and inflammation. These results suggested ALA played a key role in regulating ER homeostasis in atherosclerosis. CI - Copyright (c) 2016 Elsevier Masson SAS. All rights reserved. FAU - Hu, Huimin AU - Hu H AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. FAU - Wang, Changyuan AU - Wang C AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. FAU - Jin, Yue AU - Jin Y AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. FAU - Meng, Qiang AU - Meng Q AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. FAU - Liu, Qi AU - Liu Q AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. FAU - Liu, Kexin AU - Liu K AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. FAU - Sun, Huijun AU - Sun H AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. Electronic address: sunhuijun@dlmedu.edu.cn. LA - eng PT - Journal Article DEP - 20160314 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (HSPA5 protein, human) RN - 0 (NF-kappa B) RN - 0 (Reactive Oxygen Species) RN - 0 (Vascular Cell Adhesion Molecule-1) RN - 0LVT1QZ0BA (Homocysteine) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - 4Y8F71G49Q (Malondialdehyde) RN - 73Y7P0K73Y (Thioctic Acid) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.7.11.1 (PERK kinase) RN - EC 2.7.11.1 (eIF-2 Kinase) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - GAN16C9B8O (Glutathione) SB - IM MH - Aorta/*pathology MH - Apoptosis/drug effects MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/*drug effects MH - Endothelial Cells/drug effects/*pathology MH - Glutathione/metabolism MH - Homocysteine/*toxicity MH - Humans MH - Intercellular Adhesion Molecule-1/metabolism MH - L-Lactate Dehydrogenase/metabolism MH - Malondialdehyde/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Models, Biological MH - NF-kappa B/metabolism MH - Oxidative Stress/*drug effects MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects MH - Superoxide Dismutase/metabolism MH - Thioctic Acid/*pharmacology MH - Transcriptional Activation/drug effects/genetics MH - Vascular Cell Adhesion Molecule-1/metabolism MH - eIF-2 Kinase/metabolism OTO - NOTNLM OT - Alpha-lipoic acid OT - ER stress OT - GSH OT - HAECs OT - Homocysteine OT - Reactive oxygen species EDAT- 2016/05/03 06:00 MHDA- 2017/02/01 06:00 CRDT- 2016/05/03 06:00 PHST- 2015/12/22 00:00 [received] PHST- 2016/02/24 00:00 [accepted] PHST- 2016/05/03 06:00 [entrez] PHST- 2016/05/03 06:00 [pubmed] PHST- 2017/02/01 06:00 [medline] AID - S0753-3322(15)30529-1 [pii] AID - 10.1016/j.biopha.2016.02.022 [doi] PST - ppublish SO - Biomed Pharmacother. 2016 May;80:63-72. doi: 10.1016/j.biopha.2016.02.022. Epub 2016 Mar 14.