Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-induced Hypertension.
From: Muscle and Aging Research Unit, Boston University School of Medicine, MA 02118, USA.
Hypertension
- Publish Date: Sep 2007
- ISSN: 1524-4563
- Volume: 50
- Issue: 3
- Pages: 489-96
- Medium: Internet
- Language: English
- Citation (JAMA): Lebrasseur Nathan K, Duhaney Toni-Ann S, De Silva Deepa S, et al. Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-induced Hypertension.. Hypertension Sep 2007;50:489-96
Abstract
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.
Mesh Headings (Keywords): Aldosterone, Animals, Blood Pressure, Extracellular Matrix, Fibrosis, Heart, Heart Rate, Hypertension, Hypertrophy, Left Ventricular, Lipid Metabolism, Matrix Metalloproteinase 2, Mice, Mice, Inbred Strains, Myocardium, Peroxisome Proliferator-Activated Receptors, Procetofen, Systole, Tissue Inhibitor of Metalloproteinase-2, Ventricular Remodeling
Check for Full Text / PubMed Unique Identifier (PMID): 17606858
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