title: Atorvastatin inhibits homocysteine-induced endoplasmic reticulum stress through activation of AMP-activated protein kinase.
abstract: OBJECTIVE
  Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a fundamental role in the initiation and development of atherosclerosis. Atorvastatin is known to exert pleiotropic effects on cardiovascular system. This study was designed to examine the effect of atorvastatin on homocysteine (Hcy)-induced activation of ER stress and the potential mechanisms regarding AMP-activated protein kinase (AMPK).
  
  
  RESULTS
  Apolipoprotein E-deficient (apoE(-/-)) mice were administrated with methionine or atorvastatin and sacrificed 2 months later for plasma tests and immunohistochemical analysis. To further study the mechanisms, human umbilical vein endothelial cells (HUVECs) were incubated with various concentrations of Hcy for 1 h, or 500 μmol/L Hcy for 1-24 h. Furthermore, we challenged HUVECs with Hcy in the presence or absence of atorvastatin, 5-amino-4-imidazolecarboxamide riboside-l-beta-D-ribofuranoside (AICAR), an AMPK agonist, and AMPK-DN that expressed a dominant-negative mutant of AMPK. Expression levels of ER stress markers were measured by real-time PCR and Western blot analysis. Our data revealed that atorvastatin prevented Hcy-induced ER stress in the aortic roots of hyperhomocysteinemic mice. In vitro study showed atorvastatin suppressed Hcy-induced ER stress in HUVECs as well. AICAR is found to have the same effect as that of atorvastatin, which could be antagonized by AMPK-DN.
  
  
  CONCLUSIONS
  Atorvastatin inhibits Hcy-induced ER stress both in vitro and in vivo. The protective effect of atorvastatin against Hcy-induced vascular injury is mediated by AMPK activation.
authors: Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China.
authors: Fang
authors: F
authors: Jia
authors: Chunfang
authors: C
authors: Wu
authors: Zhenyue
authors: Z
authors: Chen
authors: Guoping
authors: G
authors: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D000069059:Atorvastatin; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006710:Homocysteine / Q000097:blood / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008055:Lipids / Q000097:blood; D051379:Mice; D016133:Polymerase Chain Reaction; D011758:Pyrroles / Q000494:pharmacology*; D012265:Ribonucleotides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D008055:Lipids; D011758:Pyrroles; D012265:Ribonucleotides; D006710:Homocysteine; D000620:Aminoimidazole Carboxamide; D000069059:Atorvastatin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide