(Applicant?s abstract): Cardiac dysfunction occurs at a higher rate in patients with diabetes mellitus, even when risk factors, like coronary artery disease, are accounted for. This proposal is designed to test the hypothesis that excessive rates of myocardial fatty acid uptake and oxidation lead to pathologic remodeling similar to that in diabetic cardiomyopathy. To this end, we have focused on the peroxisome proliferator-activated receptor a (PPARa), a nuclear receptor transcription factor that activates cardiac fatty acid (FA) utilization pathways. Transgenic mice that over-express PPARa in a cardiac-specific manner (MHC-PPARa mice) have been generated. Because PPARa plays a critical role in regulating the expression of genes encoding cellular FA utilization enzymes, it is predicted that rates of FA import and oxidation will be increased in the hearts of MHC-PPARa mice, which in turn may lead to cardiac hypertrophy, dysfunction and ultimately failure.
The specific aims of this proposal are 1) To characterize the metabolic phenotype of MHC-PPARa mice. 2) To characterize cardiac structure and function in MHC-PPARa mice. 3) To compare the myocardial phenotype of MHC-PPARa mice to the streptozotocin-induced model of diabetic cardiomyopathy and to determine the role of altered substrate utilization in the genesis and severity of cardiac dysfunction.
| Finck, Brian N; Lehman, John J; Leone, Teresa C et al. (2002) The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121-30 |
| Finck, Brian N; Kelly, Daniel P (2002) Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart. J Mol Cell Cardiol 34:1249-57 |
