The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus
Brian N. Finck, John J. Lehman, Teresa C. Leone, Michael J. Welch, Michael J. Bennett, Attila Kovacs, Xianlin Han, Richard W. Gross, Ray Kozak, Gary D. Lopaschuk, Daniel P. Kelly
Brian N. Finck, John J. Lehman, Teresa C. Leone, Michael J. Welch, Michael J. Bennett, Attila Kovacs, Xianlin Han, Richard W. Gross, Ray Kozak, Gary D. Lopaschuk, Daniel P. Kelly
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Article

The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus

Abstract

Recent evidence has defined an important role for PPARα in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARα in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARα (MHC-PPAR) were produced and characterized. The expression of PPARα target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice, a metabolic phenotype strikingly similar to that of the diabetic heart. MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy including ventricular hypertrophy, activation of gene markers of pathologic hypertrophic growth, and transgene expression–dependent alteration in systolic ventricular dysfunction. These results demonstrate that (a) PPARα is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARα regulatory pathways results in a reciprocal repression of glucose uptake and utilization pathways, and (c) derangements in myocardial energy metabolism typical of the diabetic heart can become maladaptive, leading to cardiomyopathy.

Authors

Brian N. Finck, John J. Lehman, Teresa C. Leone, Michael J. Welch, Michael J. Bennett, Attila Kovacs, Xianlin Han, Richard W. Gross, Ray Kozak, Gary D. Lopaschuk, Daniel P. Kelly

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Altered expression of genes involved in glucose utilization pathways in ...
Altered expression of genes involved in glucose utilization pathways in MHC-PPAR heart. The graphs represent the results of Northern blot analyses performed with total RNA isolated from the cardiac ventricles of MHC-PPAR or littermate NTG mouse hearts. The blots were sequentially hybridized with radiolabeled cDNA probes for GLUT4, GLUT1, PFK, and pyruvate dehydrogenase kinase 4 (PDK4). Bars represent mean mRNA levels as determined by phosphorimager analysis (n ≥ 7 for each group) corrected to the GAPDH signal and normalized to that of the NTG mice treated with control chow (= 100 or 1.0). Groups receiving a 7-day course of Wy-14,643 are denoted at the bottom of each graph. Top: Representative autoradiographs of Western blot analyses using anti-GLUT4 or anti-GLUT1 antibodies with protein extracts containing total cell membrane−enriched fractions of cardiac ventricle from MHC-PPAR mice and NTG littermates. *P < 0.05 versus NTG littermate mice fed control chow. **P < 0.05 versus MHC-PPAR mice fed control chow and NTG mice. Bars represent the mean of at least seven individual animals.