PT  - JOURNAL ARTICLE
AU  - Reeba K. Vikramadithyan
AU  - Kumiko Hirata
AU  - Hiroaki Yagyu
AU  - Yunying Hu
AU  - Ayanna Augustus
AU  - Shunichi Homma
AU  - Ira J. Goldberg
TI  - Peroxisome Proliferator-Activated Receptor Agonists Modulate Heart Function in Transgenic Mice with Lipotoxic Cardiomyopathy
AID  - 10.1124/jpet.104.080259
DP  - 2005 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 586--593
VI  - 313
IP  - 2
4099  - http://jpet.aspetjournals.org/content/313/2/586.short
4100  - http://jpet.aspetjournals.org/content/313/2/586.full
SO  - J Pharmacol Exp Ther2005 May 01; 313
AB  - hLpLGPI 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. hLpLGPI 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. The American Society for Pharmacology and Experimental Therapeutics