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(Hypertension. 2007;50:489.)
© 2007 American Heart Association, Inc.

Original Articles

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

Nathan K. LeBrasseur; Toni-Ann S. Duhaney; Deepa S. De Silva; Lei Cui; Peter C. Ip; Lija Joseph; Flora Sam

From the Whitaker Cardiovascular Institute (T.-A.S.D., D.S.D.S., L.C., P.C.I., F.S.), Muscle and Aging Research Unit (N.K.L.B.), and the Department of Pathology (L.J.), Boston University School of Medicine, Boston, Mass.

Correspondence to Flora Sam, MD, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany St, Room W507, Boston, MA 02118. E-mail flora.sam{at}bmc.org

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- 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-ß, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator–activated receptor-, peroxisome proliferator–activated receptor- coactivator-1 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.

Key Words: fibrosis • aldosterone • hypertension • cardiac remodeling • matrix metalloproteinases • peroxisome proliferator–activated receptor-

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