title: Pravastatin attenuates left ventricular remodeling and diastolic dysfunction in angiotensin II-induced hypertensive mice.
abstract: BACKGROUND
  A substantial proportion of patients with heart failure have a normal ejection fraction and diastolic dysfunction. However, there are few data available to guide the therapy of these patients. The effects of statins on cardiac remodeling are well documented in animal models and it is reported that statin therapy revealed a survival benefit in patients with diastolic heart failure (DHF). However, the exact mechanisms of statins possibly explaining the decreased cardiovascular morbidity and mortality in patients with DHF have not been elucidated.
  
  
  METHODS
  We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or pravastatin in daily doses, which did not lower the serum cholesterol levels and blood pressure.
  
  
  RESULTS
  Pravastatin improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of left ventricular hypertrophy and remodeling. However, statin treatment showed no effect on the increased systolic blood pressure or cholesterol levels by angiotensin II infusion. The cardioprotective effects of pravastatin were closely associated with the downregulation of collagen I, transforming growth factor-beta, matrix metalloproteinases-2 and -3, atrial natriuretic factor, interleukin-6, tumor necrosis factor-alpha, ROCK1 gene expression, and the upregulation of endothelial nitric oxide synthase gene expression.
  
  
  CONCLUSIONS
  The beneficial effects of pravastatin on DHF and structural remodeling are through cholesterol- independent mechanism of statins or "pleiotropic" effects of statins involving improving or restoring endothelial function and decreasing vascular inflammation. These findings suggest the potential involvement of ROCK1. Thus, treatment with pravastatin might be beneficial in patients with DHF.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Zhujie
authors.initials: Z
authors.lastname: Xu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Akino
authors.forename: Hisao
authors.initials: H
authors.lastname: Onozuka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005355:Fibrosis / Q000503:physiopathology / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D054144:Heart Failure, Diastolic / Q000188:drug therapy* / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017035:Pravastatin / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000804:Angiotensin II; D002784:Cholesterol; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D017035:Pravastatin