title: Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure.
abstract: OBJECTIVE
  Oxidative stress is implicated in the pathogenesis of heart failure and affects the activity of matrix metalloproteinases (MMPs). We have now investigated the role of MMPs and their tissue inhibitors (TIMPs) in the transition from compensated left ventricular (LV) hypertrophy to heart failure as well as the effects of pravastatin on this transition in a rat model.
  
  
  METHODS
  Dahl salt-sensitive rats were fed a high-salt (8% NaCl) diet and treated with pravastatin (50 or 100 mg/kg per day) or vehicle from 7 weeks of age.
  
  
  RESULTS
  Pravastatin did not attenuate LV hypertrophy apparent at 12 or 18 weeks of age. However, the high dose of this drug markedly improved indices of diastolic function (early diastolic myocardial velocity) and systolic function (LV fractional shortening) at 18 weeks of age and increased the survival rate. It also prevented a decrease in the ratio of reduced to oxidized glutathione and an increase in NADPH oxidase activity in the left ventricle induced by the high-salt diet. The activities of MMP2 and MMP9 and the abundance of TIMP1 and TIMP2 in LV tissue were increased at 18 weeks of age, and pravastatin also prevented these changes.
  
  
  CONCLUSIONS
  Although pravastatin did not attenuate LV hypertrophy, it prevented the transition from compensated hypertrophy to heart failure in this rat model. This effect of pravastatin may result from a reduction both in the level of oxidative stress and in MMP activity in the heart.
authors.affiliation: Department of Cardiovascular Genome Science, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Sahoko
authors.initials: S
authors.lastname: Ichihara
authors.forename: Akiko
authors.initials: A
authors.lastname: Noda
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
authors.forename: Koji
authors.initials: K
authors.lastname: Obata
authors.forename: Jinglan
authors.initials: J
authors.lastname: Xu
authors.forename: Gaku
authors.initials: G
authors.lastname: Ichihara
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokota
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D009206:Myocardium / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D017035:Pravastatin / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020303:Rats, Inbred Dahl; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D005353:Fibronectins; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D019715:Tissue Inhibitor of Metalloproteinase-1; D020097:Natriuretic Peptide, Brain; D019716:Tissue Inhibitor of Metalloproteinase-2; D009320:Atrial Natriuretic Factor; D003094:Collagen; D019255:NADPH Oxidases; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D018995:Myosin Heavy Chains; D005978:Glutathione; D017035:Pravastatin