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Received for publication November 8, 2004.
Revised December 17, 2004.
Accepted for publication January 20, 2005.
hLpLGPI transgenic mice that over express human lipoprotein lipase (LpL) with a glycosylphosphatidylinositol anchor on cardiomyocytes develop lipotoxic cardiomyopathy associated with increased cardiac uptake of plasma lipids. We hypothesized that PPAR
, PPAR
or a PPAR/ 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 (10 mg/kg/day) for 16 days. Rosiglitazone reduced plasma triglyceride (TG) from 107.63 ± 6.98 to 77.61 ± 3.98 mg/dl while 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 TNF, 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 CPT-1 and FATP-1 gene expression were increased with fenofibrate and DRF2655 treatment, no change in expression of these genes with rosiglitazone treatment. Rosiglitazone and DRF2655 reduced TG uptake by the heart, fenofibrate treatment increased fatty acid uptake. Thus, in a lipotoxic cardiomyopathy mouse model, a PPAR agonist reduced cardiac lipid and markers of cardiomyopathy while an agonist of PPAR 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.
Key words:
PPAR, cardiomyopahty, heart failure, lipid, lipotoxicity, triglyceride
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