title: Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-γ).
abstract: BACKGROUND
  Previous studies have shown that the activation of advanced glycation end products (AGEs) contributed to the cardiac fibrosis in diabetic patients. Although it had been reported that statins have beneficial effects on cardiac fibrosis in hypertension and myocardial ischemia models, their effects on AGEs models have not been studied. We aimed to investigate the effects of atorvastatin (Ator) on the AGEs-induced cardiac fibrosis both in vitro and vivo.
  
  
  METHODS
  Male Sprague-Dawley rats were randomly divided into four groups: Control, AGEs, Ator or AGEs+Ator. The cardiac function was evaluated with the echocardiography at the second and the third month. Fibrosis area, α-SMA and RAGE expression in cardiac tissue were measured. For in vitro study, rat cardiac fibroblasts were treated with PD98059 (ERK inhibitor), Ator or Ator+GW9662 (PPAR-γ antagonist), and then were stimulated with AGEs. Fibroblasts proliferation, ERK1/2, phosphorylated ERK1/2, α-SMA, and RAGE expression were studied.
  
  
  RESULTS
  Compared with the control group, in vivo treatment with Ator significantly retarded the AGEs-induced diastolic function and attenuated cardiac fibrosis, α-SMA, and RAGE over expression induced by AGEs. Consistently, Ator prominently downregulated RAGE and α-SMA, while inhibited phosphorylation of ERK1/2 and fibroblast proliferation induced by AGEs in vitro. The GW9662 neutralized these effects of Ator on cardiac fibroblasts stimulated by AGEs.
  
  
  CONCLUSIONS
  In this study, we demonstrated that AGEs-induced fibroblast proliferation and differentiation were dependent on AGEs-RAGE-ERK1/2 pathway and that atorvastatin could block this pathway via activating PPAR-γ.
authors.affiliation: Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China. Electronic address: lhw19656@sina.com.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Emergency, Beijing Friendship Hospital, Capital Medical University, Beijing, China. Electronic address: 13520240749@163.com.
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Xuhua
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Shumei
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Su
mesh_terms: D000199:Actins / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005355:Fibrosis; D017127:Glycation End Products, Advanced / Q000009:adverse effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000517:prevention & control*; D006334:Heart Function Tests; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D000199:Actins; D000813:Anilides; D000069059:Atorvastatin; D017127:Glycation End Products, Advanced; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047495:PPAR gamma; D000067759:Receptor for Advanced Glycation End Products; C457499:2-chloro-5-nitrobenzanilide; C000593874:Ager protein, rat; C498862:Acta2 protein, rat
keywords: Advanced glycation end products; Atorvastatin; PPAR-γ; RAGE