Key result
Cardiac PPARα overexpression in mice increases palmitate oxidation ~64%, causing hypertrophy and systolic dysfunction.
Why the study?
The role of PPARα in the metabolic and functional derangements of diabetic cardiomyopathy was investigated to understand its contribution to cardiac energy metabolism.
Does cardiac-restricted overexpression of PPARα induce a metabolic and functional phenotype similar to diabetic cardiomyopathy in mice?
Does cardiac-restricted overexpression of PPARα induce a metabolic and functional phenotype similar to diabetic cardiomyopathy in mice?
Answers are grounded in this paper and cite their sources.
Cardiac-restricted overexpression of PPARα in mice induces metabolic derangements and cardiomyopathy similar to that seen in diabetes, highlighting PPARα's role in myocardial energy metabolism.
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.
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Finck et al. (2002) studied Diabetic cardiomyopathy. Cardiac-restricted overexpression of PPARα vs. Non-transgenic littermates was evaluated on Myocardial palmitate oxidation rate (nmol/min/g dry weight) (p=<0.05). Cardiac-restricted overexpression of PPARα in mice increased myocardial palmitate oxidation by 64% and decreased glucose oxidation by 63%, leading to ventricular hypertrophy and systolic dysfunction mimicking diabetic cardiomyopathy.
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