title: A critical role for peroxisomal proliferator-activated receptor-alpha nuclear receptors in the development of cardiomyocyte degeneration and necrosis.
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.
authors.affiliation: Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Eastern Point Rd., Groton, CT 06340, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pruimboom-Brees
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Haghpassand
authors.forename: Lori
authors.initials: L
authors.lastname: Royer
authors.forename: Dominique
authors.initials: D
authors.lastname: Brees
authors.forename: Charles
authors.initials: C
authors.lastname: Aldinger
authors.forename: William
authors.initials: W
authors.lastname: Reagan
authors.forename: Jatinder
authors.initials: J
authors.lastname: Singh
authors.forename: Roy
authors.initials: R
authors.lastname: Kerlin
authors.forename: Christopher
authors.initials: C
authors.lastname: Kane
authors.forename: Scott
authors.initials: S
authors.lastname: Bagley
authors.forename: Cheryl
authors.initials: C
authors.lastname: Hayward
authors.forename: James
authors.initials: J
authors.lastname: Loy
authors.forename: Peter
authors.initials: P
authors.lastname: O'Brien
authors.forename: Omar L
authors.initials: OL
authors.lastname: Francone
mesh_terms: D042962:Acyl-CoA Oxidase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002995:Clofibric Acid / Q000494:pharmacology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D006335:Heart Injuries / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D047493:PPAR alpha / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D020675:Peroxisomes / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D002995:Clofibric Acid; D042962:Acyl-CoA Oxidase