期刊
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
卷 50, 期 1, 页码 25-34出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0b013e31804b4163
关键词
PPAR delta; congestive heart failure; metabolism; magnetic resonance imaging
Previously, it was shown that selective deletion of peroxisome proliferator activated receptor 8 (PPAR delta) in the heart resulted in a cardiac lipotoxicity, hypertrophy, and heart failure. The aim of the present study was to determine the effects of chronic and selective pharmacological activation of PPAR delta in a model of congestive heart failure. PPAR delta-specific agonist treatment (GW610742X at 30 and 100 mg/kg/day for 6-9 weeks) was initiated immediately postrnyocardial infarction (MI) in Sprague-Dawley rats. Magnetic resonance imaging/spectroscopy was used to assess cardiac function and energetics. A 1-C-13 glucose clamp was performed to assess relative cardiac carbohydrate versus fat oxidation. Additionally, cardiac hemodynamics and reverse-transcription polymerase chain reaction gene expression analysis was performed. MI rats had significantly reduced left ventricle (IV) ejection fractions and whole heart phosphocreatine/adenosine triphosphate ratio compared with Sham animals (reduction of 43% and 14%, respectively). However, GW610742X treatment had no effect on either parameter. In contrast, the decrease in relative fat oxidation rate observed in both IV and right ventricle (RV) following MI (decrease of 58% and 54%, respectively) was normalized in a dose-dependent manner following treatment with GW610742X. These metabolic changes were associated with an increase in lipid transport/metabolism target gene expression (eg, CD36, CPT 1, UCP3). Although there was no difference between groups in IV weight or infarct size measured upon necropsy, there was a dramatic reduction in RV hypertrophy and lung congestion (decrease of 22-48%, P < 0.01) with treatment which was associated with a > 7-fold decrease (P < 0.05) in aterial natriurefic peptide gene expression in RV. Diuretic effects were not observed with GW610742X. In conclusion, chronic treatment with a selective PPAR delta agonist normalizes cardiac substrate metabolism and reduces RV hypertrophy and pulmonary congestion consistent with improvement in congestive heart failure.
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