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Nuclear Receptors in the Development of Cardiomyocyte Degeneration and Necrosis
From Pfizer Global Research and Development, Groton, Connecticut
Peroxisomal proliferator-activated receptor (PPAR)-
is a ligand-activated transcriptional factor that regulates genes involved in lipid metabolism and energy homeostasis. PPAR- activators, including fibrates, have been used to treat dyslipidemia for several decades. In contrast to their known effects on lipids, the pharmacological consequences of PPAR- activation on cardiac metabolism and function are not well understood. Therefore, we evaluated the role that PPAR- receptors play in the heart. Our studies demonstrate that activation of PPAR- receptors using a selective PPAR- ligand results in cardiomyocyte necrosis in mice. Studies in PPAR--deficient mice demonstrated that cardiomyocyte necrosis is a consequence of the activation of PPAR- receptors. Cardiac fatty acyl-CoA oxidase mRNA levels increased at doses in which cardiac damage was observed and temporally preceded cardiomyocyte degeneration, suggesting that peroxisomal ß-oxidation correlates with the appearance of microscopic injury and cardiac injury biomarkers. Increased myocardial oxidative stress was evident in mice treated with the PPAR- agonists coinciding with increased peroxisomal biomarkers of fatty acid oxidation. These findings suggest that activation of PPAR- leads to increased cardiac fatty acid oxidation and subsequent accumulation of oxidative stress intermediates resulting in cardiomyocyte necrosis.
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