PPARdelta activation normalizes cardiac substrate metabolism and reduces right ventricular hypertrophy in congestive heart failure.
Previously, it was shown that selective deletion of peroxisome proliferator activated receptor delta (PPARdelta) 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 PPARdelta in a model of congestive heart failure. PPARdelta-specific agonist treatment (GW610742X at 30 and 100 mg/kg/day for 6-9 weeks) was initiated immediately postmyocardial infarction (MI) in Sprague-Dawley rats. Magnetic resonance imaging/spectroscopy was used to assess cardiac function and energetics. A 1-(13)C 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 (LV) 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 LV 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, CPT1, UCP3). Although there was no difference between groups in LV 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 natriuretic peptide gene expression in RV. Diuretic effects were not observed with GW610742X. In conclusion, chronic treatment with a selective PPARdelta agonist normalizes cardiac substrate metabolism and reduces RV hypertrophy and pulmonary congestion consistent with improvement in congestive heart failure.
Jucker
Beat M
BM
Cardiovascular and Urogenital Center of Excellence for Drug Discovery, and Genomics Research, GlaxoSmithKline, King of Prussia, PA 19406, USA.
Doe
Christopher P
CP
Schnackenberg
Christine G
CG
Olzinski
Alan R
AR
Maniscalco
Kristeen
K
Williams
Carolyn
C
Hu
Tom C-C
TC
Lenhard
Stephen C
SC
Costell
Melissa
M
Bernard
Roberta
R
Sarov-Blat
Lea
L
Steplewski
Klaudia
K
Willette
Robert N
RN
D000818:Animals; D001692:Biological Transport; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D011654:Pulmonary Edema / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016277:Ventricular Function, Left / Q000187:drug effects
D008055:Lipids; D047494:PPAR delta