Peroxisome proliferator-activated receptor α-independent actions of Fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload

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) alpha activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPAR alpha-independent effects in response to chronic pressure overload ( PO). Wild-type and PPAR alpha-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 alpha-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 alpha, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPAR alpha-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 alpha-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 alpha-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPAR alpha, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPAR alpha agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart.