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Peroxisome Proliferator-Activated Receptor Agonists Modulate Heart Function in Transgenic Mice with Lipotoxic Cardiomyopathy
hLpL GPI transgenic mice that overexpress human lipoprotein lipase (hLpL) with a glycosylphosphatidylinositol anchor on cardiomyocytes develop lipotoxic cardiomyopathy associated with increased cardiac uptake of plasma lipids. We hypothesized that peroxisome proliferator-activated receptor (PPAR)α,...
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Published in: | The Journal of pharmacology and experimental therapeutics 2005-05, Vol.313 (2), p.586-593 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | hLpL GPI transgenic mice that overexpress human lipoprotein lipase (hLpL) with a glycosylphosphatidylinositol anchor on cardiomyocytes
develop lipotoxic cardiomyopathy associated with increased cardiac uptake of plasma lipids. We hypothesized that peroxisome
proliferator-activated receptor (PPAR)α, PPARγ, or a PPARα/γ agonist would alter cardiac function by modulating lipid uptake
by the heart. hLpL GPI mice were administered rosiglitazone (10 mg/kg/day), fenofibrate (100 mg/kg/day), or DRF2655, an alkoxy propanoic acid analog
(10 mg/kg/day), for 16 days. Rosiglitazone reduced plasma triglyceride (TG) from 107.63 ± 6.98 to 77.61 ± 3.98 mg/dl, whereas
fenofibrate had no effect. DRF2655 reduced TG to 33.17 ± 4.12 mg/dl. Rosiglitazone and DRF2655 decreased heart TG and total
cholesterol; fenofibrate had no effect. Molecular markers for cardiac dysfunction, atrial natriuretic factor, brain natriuretic
peptide, and tumor necrosis factor-α were decreased with rosiglitazone and increased with fenofibrate. Echocardiographic measurements
showed reduced fractional shortening and increased left ventricular systolic dimension with fenofibrate. No changes in these
parameters were observed with rosiglitazone or DRF2655 treatment. Muscle-specific carnitine palmitoyltransferase-1 and fatty
acid transporter protein-1 gene expression were increased with fenofibrate and DRF2655 treatment; no change in expression
of these genes was noted with rosiglitazone treatment. Rosiglitazone and DRF2655 reduced TG uptake by the heart, and fenofibrate
treatment increased fatty acid uptake. Thus, in a lipotoxic cardiomyopathy mouse model, a PPARγ agonist reduced cardiac lipid
and markers of cardiomyopathy, whereas an agonist of PPARα did not improve cardiac lipids and worsened heart function. These
changes were paralleled by alterations in heart lipid uptake. Overall, PPAR activators exhibit differential effects in this
model of lipotoxic dilated cardiomyopathy. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.104.080259 |