TY - JOUR
T1 - Peroxisome proliferator-activated receptor α-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload
AU - Duhaney, Toni Ann S.
AU - Cui, Lei
AU - Rude, Mary K.
AU - Lebrasseur, Nathan K.
AU - Ngoy, Soeun
AU - De Silva, Deepa S.
AU - Siwik, Deborah A.
AU - Liao, Ronglih
AU - Sam, Flora
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/5
Y1 - 2007/5
N2 - 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) α activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPARα-independent effects in response to chronic pressure overload (PO). Wild-type and PPARα-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 PPARα-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 PPARα, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPARα-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 PPARα-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 PPARα-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPARα, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPARα agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart.
AB - 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) α activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPARα-independent effects in response to chronic pressure overload (PO). Wild-type and PPARα-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 PPARα-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 PPARα, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPARα-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 PPARα-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 PPARα-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPARα, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPARα agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart.
KW - Fibrosis
KW - Matrix metalloproteinases
KW - Peroxisome proliferator-activated receptor
KW - Pressure overload
KW - Ventricular remodeling
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U2 - 10.1161/HYPERTENSIONAHA.107.086926
DO - 10.1161/HYPERTENSIONAHA.107.086926
M3 - Article
C2 - 17353509
AN - SCOPUS:34247880263
SN - 0194-911X
VL - 49
SP - 1084
EP - 1094
JO - Hypertension
JF - Hypertension
IS - 5
ER -