title: Atorvastatin reduces myocardial fibrosis in a rat model with post-myocardial infarction heart failure by increasing the matrix metalloproteinase-2/tissue matrix metalloproteinase inhibitor-2 ratio.
abstract: BACKGROUND
  The cholesterol-lowering statin drugs have some non-lipid-lowering effects, such as inhibiting myocardial remodeling. However, the underlying mechanism is still unclear.
  
  
  METHODS
  The left anterior descending coronary artery was ligated to establish a rat model of heart failure, and the rats were divided into a sham operation (SO) group, myocardial infarction model (MI) group, and MI-atorvastatin group. Changes in hemodynamic parameters were recorded after the final drug administration. Histological diagnosis was made by reviewing hematoxylin and eosin (HE) stained tissue. Real-time quantitative polymerase chain reaction (PCR) was performed to determine the expressions of type I and type III collagen, matrix metalloproteinase-2 (MMP-2), and tissue matrix metalloproteinase inhibitor-2 (TIMP-2). Further, primary rat cardiac fibroblasts were cultured and the MTT assay was performed to determine the effect of atorvastatin on cardiac fibroblast proliferation.
  
  
  RESULTS
  The model of heart failure was established and the results of HE staining and Masson's trichrome staining revealed that the rats in the heart failure group showed obvious hyperplasia of fibrotic tissue, which was significantly reduced in the atorvastatin group. Real-time quantitative PCR showed that the MI group showed a significantly increased expression of type I and type III collagen, MMP-2, and TIMP-2, but a significantly reduced MMP-2/TIMP-2 ratio. Compared with the MI group, the atorvastatin group showed significantly reduced expression of type I and III collagen, unchanged expression of MMP-2, significantly reduced expression of TIMP-2, and an increased MMP-2/TIMP-2 ratio. We further found that atorvastatin significantly inhibited the Ang II-induced fibroblast proliferation and the expression of type I and type III collagen in cardiac fibroblasts while increasing the MMP-2/TIMP-2 ratio.
  
  
  CONCLUSIONS
  These data suggest that atorvastatin can inhibit cardiac fibroblast proliferation and enhance collagen degradation by increasing the MMP-2/TIMP-2 ratio, thereby inhibiting the formation of myocardial fibrosis in rats with heart failure after myocardial infarction.
authors.affiliation: Department of Cardiology, the Second Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: An
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Yu-quan
authors.initials: YQ
authors.lastname: He
authors.forename: Ning
authors.initials: N
authors.lastname: Dong
authors.forename: Li-li
authors.initials: LL
authors.lastname: Ge
authors.forename: Shu-mei
authors.initials: SM
authors.lastname: Li
authors.forename: Wen-qi
authors.initials: WQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D000069059:Atorvastatin; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat