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(Hypertension. 2007;49:1084.)
© 2007 American Heart Association, Inc.

Original Articles

Peroxisome Proliferator-Activated Receptor –Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload

Toni-Ann S. Duhaney; Lei Cui; Mary K. Rude; Nathan K. Lebrasseur; Soeun Ngoy; Deepa S. De Silva; Deborah A. Siwik; Ronglih Liao; Flora Sam

From the Whitaker Cardiovascular Institute (T-A.S.D., L.C., M.K.R., S.N., D.S.D.S., D.A.S., R.L., F.S.) and Muscle and Aging Research Unit (N.K.L.), Boston University School of Medicine, Mass.

Correspondence to Flora Sam, Whitaker Cardiovascular Institute, Boston University School of Medicine, 650 Albany St, Room X704, Boston, MA 02118. E-mail flora.sam{at}bmc.org

Progressive cardiac remodeling is characterized by subsequent chamber hypertrophy, enlargement, and pump dysfunction. It is also associated with increased cardiac fibrosis and matrix turnover. Interestingly, peroxisome proliferator-activated receptor (PPAR) activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPAR-independent effects in response to chronic pressure overload (PO). Wild-type and PPAR-deficient mice were subjected to chronic PO caused by ascending aortic constriction to test the role of fenofibrates in chronic, progressive cardiac remodeling by a PPAR-independent mechanism. Mice were randomized to regular chow or chow-containing fenofibrate (100 mg/kg of body weight per day) for 1 week before and 8 weeks after ascending aortic constriction. In the presence of PPAR, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPAR-deficient mice treated with fenofibrate had increased mortality, significantly adverse left ventricular end diastolic (3.4±0.1 versus 4.2±0.1 mm) and end systolic (1.5±0.2 versus 2.5±0.2 mm) dimensions, and fractional shortening (57±3% versus 40±3%). Fenofibrate also increased myocardial hypertrophy, cardiac fibrosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2 in PO PPAR-deficient mice. Fenofibrate inhibited matrix metalloproteinase activity in vitro and aldosterone-induced increases in extracellular signal-regulated kinase phosphorylation. Thus, fenofibrate improved cardiac remodeling in chronic PO mice. However, in PPAR-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPAR, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPAR agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart.

Key Words: fibrosis • pressure overload • ventricular remodeling • peroxisome proliferator-activated receptor • matrix metalloproteinases

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