title: Atorvastatin attenuates atherosclerotic plaque destabilization by inhibiting endoplasmic reticulum stress in hyperhomocysteinemic mice.
abstract: Endoplasmic reticulum (ER) stress has been suggested to play a role in the progression of plaque vulnerability and the occurrence of acute complications of coronary atherosclerosis. Atorvastatin is known to exert pleiotropic effects on the cardiovascular system. The present study aimed to examine the stabilizing effects of atorvastatin on vulnerable plaques within hyperhomocysteinemic apolipoprotein E‑deficient (ApoE‑/‑) mice, and to investigate the potential mechanisms underlying ER stress in ApoE‑/‑ mice and macrophages. In the present study, ApoE‑/‑ mice were administrated methionine or atorvastatin, and were sacrificed after 2 months. Necrotic core size, collagen content and inflammatory cytokine infiltration were subsequently measured in the aortic lesions, in order to investigate plaque stability. Treatment with atorvastatin decreased the number and size of necrotic cores, increased collagen content, and downregulated tumor necrosis factor (TNF)‑α and matrix metalloproteinase (MMP)‑9 mRNA expression, as compared with the methionine group. Immunohistochemical analysis indicated that atorvastatin administration prevented ER stress activation in aortic lesions of hyperhomocysteinemic mice. Furthermore, macrophages were challenged with homocysteine (Hcy) in the presence or absence of atorvastatin and thapsigargin (an ER stress inducer). Atorvastatin suppressed Hcy‑induced ER stress, and downregulated TNF‑α and MMP‑9 mRNA expression in the macrophages. Conversely, thapsigargin attenuated the inhibitory effects of atorvastatin against Hcy‑induced TNF‑α and MMP‑9 expression. These results indicated that hyperhomocysteinemia may promote atherosclerotic plaque development and instability. In addition, atorvastatin was able to improve atherosclerotic plaque stability in hyperhomocysteinemic mice by inhibiting ER stress.
authors.affiliation: Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Jia
authors.affiliation: Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D000069059:Atorvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006710:Homocysteine / Q000097:blood / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000188:drug therapy; D000067996:RAW 264.7 Cells; D060888:Real-Time Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D014409:Tumor Necrosis Factor-alpha; D006710:Homocysteine; D019284:Thapsigargin; D000069059:Atorvastatin; D008715:Methionine; D020780:Matrix Metalloproteinase 9