1. A Critical Role for Peroxisomal Proliferator-Activated Receptor-α Nuclear Receptors in the Development of Cardiomyocyte Degeneration and Necrosis
- Author
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Lori Royer, Roy L. Kerlin, Cheryl Myers Hayward, Ingrid M. Pruimboom-Brees, Jatinder Singh, Peter J. O'Brien, William J. Reagan, James Kenneth Loy, Christopher D. Kane, Dominique Brees, Charles E. Aldinger, Mehrdad Haghpassand, Omar L. Francone, and Scott W. Bagley
- Subjects
medicine.medical_specialty ,Peroxisome proliferator-activated receptor ,Biology ,medicine.disease_cause ,Pathology and Forensic Medicine ,Clofibric Acid ,Mice ,Necrosis ,Internal medicine ,medicine ,Peroxisomes ,Acyl-CoA oxidase ,Animals ,Myocytes, Cardiac ,PPAR alpha ,RNA, Messenger ,Receptor ,Beta oxidation ,chemistry.chemical_classification ,Mice, Knockout ,Anticholesteremic Agents ,Fatty Acids ,Lipid metabolism ,Peroxisome ,Lipid Metabolism ,Oxidative Stress ,Endocrinology ,chemistry ,Nuclear receptor ,Heart Injuries ,lipids (amino acids, peptides, and proteins) ,Acyl-CoA Oxidase ,Cardiomyopathies ,Oxidation-Reduction ,Oxidative stress ,Biomarkers ,Regular Articles - Abstract
Peroxisomal proliferator-activated receptor (PPAR)-alpha is a ligand-activated transcriptional factor that regulates genes involved in lipid metabolism and energy homeostasis. PPAR-alpha 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-alpha activation on cardiac metabolism and function are not well understood. Therefore, we evaluated the role that PPAR-alpha receptors play in the heart. Our studies demonstrate that activation of PPAR-alpha receptors using a selective PPAR-alpha ligand results in cardiomyocyte necrosis in mice. Studies in PPAR-alpha-deficient mice demonstrated that cardiomyocyte necrosis is a consequence of the activation of PPAR-alpha 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 beta-oxidation correlates with the appearance of microscopic injury and cardiac injury biomarkers. Increased myocardial oxidative stress was evident in mice treated with the PPAR-alpha agonists coinciding with increased peroxisomal biomarkers of fatty acid oxidation. These findings suggest that activation of PPAR-alpha leads to increased cardiac fatty acid oxidation and subsequent accumulation of oxidative stress intermediates resulting in cardiomyocyte necrosis.
- Published
- 2006