Cardiac-restricted overexpression of PPARα in mice increased myocardial fatty acid oxidation by 64% and decreased glucose oxidation by 63%, mimicking the metabolic phenotype of diabetic cardiomyopathy.
Absolute Event Rate: 294% vs 179%
p-value: p=<0.05
Recent evidence has defined an important role for PPARalpha in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARalpha in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARalpha (MHC-PPAR) were produced and characterized. The expression of PPARalpha 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) PPARalpha is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARalpha 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.
Finck et al. (Tue,) conducted a other in Diabetic cardiomyopathy. Cardiac-restricted overexpression of PPARα vs. Nontransgenic 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 fatty acid oxidation by 64% and decreased glucose oxidation by 63%, mimicking the metabolic phenotype of diabetic cardiomyopathy.