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

Abstract

Abstract-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 (3.4Ϯ0.1 versus 4.2Ϯ0.1 mm) and end systolic (1.5Ϯ0.2 versus 2.5Ϯ0.2 mm) dimensions, and fractional shortening (57Ϯ3% versus 40Ϯ3%). 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. (Hypertension. 2007; 49:1084-1094.)

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

“…30 We previously showed that aldosterone increases myocyte MMP activity and extracellular signal-regulated kinase phosphorylation 11 and may be inhibited by fenofibrate. 19 Similar to other in vivo models of HF (ie, mice subjected to pressure overload or angiotensin II infusions), aldosterone administration induces a proinflammatory and a profibrotic phenotype. 10,31 In our study, aldosterone-induced LVH was associated with an increased MMP-2/TIMP-2 ratio.…”

“…32,33 Similar to the findings of other studies, 21,34,35 aldosteronemediated increases in the MMP-2/TIMP-2 ratio was associated with significant interstitial fibrosis, which was attenuated by fenofibrate. Fenofibrate may exert PPAR-␣-independent effects by increasing MMP-2 and decreasing TIMP-2 expression, 19 resulting in LVH and fibrosis. Similarly, the MMP-2 gene plays a critical role in myocyte hypertrophy, 36 pressure overload-induced LVH, 10,31 and in the promotion of interstitial fibrosis.…”

“…18 We previously demonstrated in isolated adult cardiomyocytes that fenofibrate inhibits MMP activity and aldosterone-stimulated increases in extracellular signal-regulated kinase phosphorylation. 19 In the present study, we used a murine model of aldosterone-induced hypertension and diastolic HF to test the hypothesis that fenofibrate exerts beneficial effects on myocardial structure, function, and matrix.…”

The PPARα Agonists Fenofibrate and CP-778875 Cause Increased β-Oxidation, Leading to Oxidative Injury in Skeletal and Cardiac Muscle in the Rat

“…However, in PPARa-deficient mice treated with fenofibrate, there was an increased mortality, adverse changes on ventricular wall dimensions, increased myocardial hypertrophy, and cardiac fibrosis (Duhaney et al 2007). Thus, in some models fenofibrate exerts a beneficial effect on cardiac FIGURE 7.-Effect of CP-778875 and fenofibrate on AOX mRNA levels in (A) liver, (B) heart, and (C) skeletal muscle.…”

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

“…In rats with aortic banding, fenofibrate treatment inhibited left ventricular hypertrophy and phenotypic changes in cardiac gene expression of endothelin-1, BNP, and β-myosin heavy chain [38] . In a model of chronic pressure overload model (transverse aortic constriction) fenofibrate showed adverse effects in PPARα-deficient mice, such as activation of MMP, increased fibrosis, left ventricular hypertrophy and increased mortality [39] . In PPARα wild type mice, fenofibrate treatment showed opposite (beneficial) effects.…”