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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Myocardial palmitate utilization is increased and FDG reduced in MHC-PPA...
Myocardial palmitate utilization is increased and FDG reduced in MHC-PPAR mice. (a) The top two panels contain representative images of 11C-palmitate and 18F-FDG uptake into myocardium as assessed by microPET in NTG and MHC-PPAR mice following a 6-hour fast. The relative amount of tracer uptake into the mouse heart 15 seconds after bolus injection of 11C-palmitate or 18F-FDG into the jugular vein is indicated by the color scale (0−100). The arrows indicate the cardiac field. As shown in the upper panel, the color field is increased into the red scale in the hearts of MHC-PPAR mice infused with 11C-palmitate, which is indicative of enhanced myocardial uptake of fatty acid. Conversely, uptake of 18F-FDG is substantially lower in hearts of MHC-PPAR mice than in those of NTG littermates. The graphs below the images contain time-activity curves for the cardiac fields. (b) Myocardial palmitate oxidation is increased and glucose oxidation reduced in MHC-PPAR mice. The oxidation of [9,10-3H]palmitate and [U-14C]glucose was assessed in isolated working hearts (as described in Methods) of MHC-PPAR (line 402-2; n = 6) or NTG littermate (n = 4) mice fed control chow. Bars represent mean (± SEM) oxidation rates expressed as nanomoles of substrate oxidized per minute per gram dry mass. *P < 0.05 versus NTG littermate mice.