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: Ingrid Pruimboom-Brees, Mehrdad Haghpassand, Lori Royer, Dominique Brees, Charles Aldinger, William Reagan, Jatinder Singh, Roy Kerlin, Christopher Kane, Scott Bagley, Cheryl Hayward, James Loy, Peter O'Brien, Omar L Francone
• Journal: The American journal of pathology (Am J Pathol) Vol. 169 Issue 3 Pg. 750-60 (Sep 2006) ISSN: 0002-9440 [Print] United States
• PMID: 16936252 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anticholesteremic Agents
• Biomarkers
• Fatty Acids
• PPAR alpha
• RNA, Messenger
• Clofibric Acid
• Acyl-CoA Oxidase

Topics

• Acyl-CoA Oxidase (biosynthesis, genetics)
• Animals
• Anticholesteremic Agents (pharmacology)
• Biomarkers (metabolism)
• Cardiomyopathies (chemically induced, genetics, metabolism, pathology)
• Clofibric Acid (pharmacology)
• Fatty Acids (genetics, metabolism)
• Heart Injuries (chemically induced, genetics, metabolism, pathology)
• Lipid Metabolism (drug effects, genetics)
• Mice
• Mice, Knockout
• Myocytes, Cardiac (metabolism, pathology)
• Necrosis (genetics, metabolism, pathology)
• Oxidation-Reduction (drug effects)
• Oxidative Stress (drug effects, genetics)
• PPAR alpha (agonists, deficiency, metabolism)
• Peroxisomes (metabolism, pathology)
• RNA, Messenger (biosynthesis, genetics)