Document Detail

Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension.
MedLine Citation:
PMID:  17606858     Owner:  NLM     Status:  MEDLINE    
Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferator-activated receptor-alpha agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (n=14) or treated with fenofibrate 100 mg/kg per day (n=12) for 1 week before and 4 weeks after surgery. Aldosterone increased systolic blood pressure in untreated mice versus saline-untreated mice (134+/-3 versus 91+/-3 mm Hg; P<0.01). This was unaffected by fenofibrate (131+/-3 mm Hg). Aldosterone increased LV end-diastolic and end-systolic dimensions, which were significantly attenuated by fenofibrate (3.8+/-0.1 versus 3.5+/-0.1 mm, and 1.5+/-0.1 versus 1.15+/-0.1 mm, respectively). Fenofibrate also decreased aldosterone-induced LV hypertrophy (LV weight/body weight, 4.1+/-0.2 versus 4.6+/-0.1 mg/g) and improved percent LV fractional shortening (67+/-7% versus 60+/-2%). Additionally, fenofibrate ameliorated the increased matrix metalloproteinase-2/tissue inhibitors of metalloproteinase-2 ratio and fibrosis seen in aldosterone-untreated hearts (P<0.05 for both). Furthermore, in aldosterone-untreated hearts, fenofibrate decreased transforming growth factor-beta, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator-activated receptor-alpha, peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression, and acetyl coenzyme A carboxylase phosphorylation (P<0.05 for all) in aldosterone-infused hearts; uncoupling protein-3 and medium-chain acyl coenzyme A dehydrogenase protein expression decreased with fenofibrate (P<0.05 and P<0.01, respectively, versus aldosterone-infused), suggesting that improved myocardial remodeling is independent of fatty acid oxidation. Thus, fenofibrate improved aldosterone-induced LV hypertrophy independently of an effect on blood pressure with decreased fibrosis and altered extracellular matrix.
Nathan K Lebrasseur; Toni-Ann S Duhaney; Deepa S De Silva; Lei Cui; Peter C Ip; Lija Joseph; Flora Sam
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-07-02
Journal Detail:
Title:  Hypertension     Volume:  50     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-08-23     Completed Date:  2007-09-18     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  489-96     Citation Subset:  IM    
Muscle and Aging Research Unit, Boston University School of Medicine, MA 02118, USA.
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MeSH Terms
Aldosterone* / pharmacology
Blood Pressure / drug effects
Extracellular Matrix / metabolism
Heart / drug effects,  physiopathology
Heart Rate / drug effects
Hypertension / chemically induced*,  pathology,  physiopathology*
Hypertrophy, Left Ventricular / pathology
Lipid Metabolism / drug effects
Matrix Metalloproteinase 2 / metabolism
Mice, Inbred Strains
Myocardium / metabolism,  pathology
Peroxisome Proliferator-Activated Receptors / agonists
Procetofen / pharmacology*
Tissue Inhibitor of Metalloproteinase-2 / metabolism
Ventricular Remodeling / drug effects*
Grant Support
Reg. No./Substance:
0/Peroxisome Proliferator-Activated Receptors; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; 49562-28-9/Procetofen; 52-39-1/Aldosterone; EC Metalloproteinase 2

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