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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Figure 1

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Increased expression of PPARα target genes in diabetic mouse myocardium....
Increased expression of PPARα target genes in diabetic mouse myocardium. (a) Bars represent mean (± SEM) mRNA levels as determined by phosphorimager analysis of Northern blots performed with RNA isolated from mouse ventricle, shown as arbitrary units (AU) corrected for GAPDH signal intensity and normalized to the value of vehicle-injected controls (= 1.0). *P < 0.05 versus vehicle-injected mice (n = 4 for each group). A representative autoradiograph of the Northern blot studies is shown at the right. Each lane contained 15 μg total RNA isolated from mice 6 weeks after an injection of saline (vehicle) or a single dose of STZ (180 mg/kg). The blot was sequentially hybridized with the radiolabeled cDNA probes shown on the left. (b) Increased expression of PPARα target genes in db/db diabetic mice. Bars represent mRNA levels shown as arbitrary units (AU) corrected for GAPDH signal intensity and normalized to the value of db/+ littermate controls (= 1.0). *P < 0.05 versus db/+ littermate controls; n = 5 for each group. A representative autoradiograph is shown at the right. Each lane contained 15 μg of ventricular total RNA isolated from 10-week-old heterozygote control (db/+) or littermate diabetic (db/db) mice.