A critical role for peroxisomal proliferator-activated receptor-alpha nuclear receptors in the development of cardiomyocyte degeneration and necrosis.
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.
Pruimboom-Brees
Ingrid
I
Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Eastern Point Rd., Groton, CT 06340, USA.
Haghpassand
Mehrdad
M
Royer
Lori
L
Brees
Dominique
D
Aldinger
Charles
C
Reagan
William
W
Singh
Jatinder
J
Kerlin
Roy
R
Kane
Christopher
C
Bagley
Scott
S
Hayward
Cheryl
C
Loy
James
J
O'Brien
Peter
P
Francone
Omar L
OL
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
D000924:Anticholesteremic Agents; D015415:Biomarkers; D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D002995:Clofibric Acid; D042962:Acyl-CoA Oxidase