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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Increased expression of PPARα target genes in hearts of transgenic mouse...
Increased expression of PPARα target genes in hearts of transgenic mouse lines (MHC-PPAR mice) that express PPARα in a cardiac-restricted manner. (a) Representative autoradiographs of Northern (top) and Western (middle) blot studies performed with heart samples from 6-week-old mice from four independent MHC-PPAR lines. At the exposure shown, endogenous PPARα could not be detected in NTG samples. FLAG-PPARα protein was detected in the transgenic mice using an antibody directed against either PPARα (shown here) or FLAG (data not shown). Cardiac-specific expression of FLAG-PPARα mRNA was confirmed by Northern blot analysis performed with multiple tissues (bottom panel represents the 402-2 line). H, heart; BAT, brown adipose tissue; SM, skeletal muscle; K, kidney; L, liver. (b) The expression of PPARα target genes is increased and inducible by PPARα activator in the hearts of MHC-PPAR mice. The graphs represent the results of Northern blot analyses performed with the probes indicated using RNA isolated from ventricle of male and female NTG or MHC-PPAR littermate mice fed control chow or a 7-day course of chow containing Wy-14,643 (0.1% wt/wt). Bars represent mean mRNA levels (arbitrary units, AU) quantified as described in Methods (n ≥ 7 mice for each group). The inset shows representative autoradiographs of Western blot analyses. *P < 0.05 versus NTG littermate mice. **P < 0.05 versus MHC-PPAR mice fed control chow and NTG mice. Far right: Bars represent mean malonyl-CoA−inhibited CPT enzyme activity (n = 3 for each group). †P < 0.05 versus NTG littermate mice.