title: Alpha-lipoic acid defends homocysteine-induced endoplasmic reticulum and oxidative stress in HAECs.
abstract: 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-κB 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, IRE1α, ATF6, P-PERK, P-eIF2α, CHOP and ATF4 induced by HCY. In addition, using GSH inhibitor, we proved ALA reduced the expressions of GRP78, ATF4 and IRE1α 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.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. Electronic address: sunhuijun@dlmedu.edu.cn.
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
mesh_terms: D001011:Aorta / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000633:toxicity*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005978:Glutathione; D006710:Homocysteine; D018799:Intercellular Adhesion Molecule-1; D007770:L-Lactate Dehydrogenase; D008315:Malondialdehyde; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D008063:Thioctic Acid; D019010:Vascular Cell Adhesion Molecule-1; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human
keywords: Alpha-lipoic acid; ER stress; GSH; HAECs; Homocysteine; Reactive oxygen species