Circulation Research. 2004;95:568-578
doi: 10.1161/01.RES.0000141774.29937.e3
doi: 10.1161/01.RES.0000141774.29937.e3
© 2004 American Heart Association, Inc.
Reviews |
Nuclear Receptor Signaling and Cardiac Energetics
From the Center for Cardiovascular Research and Departments of Medicine (J.M.H., D.P.K.), Molecular Biology and Pharmacology (D.P.K.), and Pediatrics (D.P.K.), Washington University School of Medicine, St Louis, Mo.
Correspondence to Daniel P. Kelly, MD, Center for Cardiovascular Research Washington University School of Medicine, St. Louis, MO 63110. E-mail dkelly{at}im.wustl.edu
This Review is part of a thematic series on Nuclear Receptor Signaling, which includes the following articles:
Nuclear Receptor Signaling and Cardiac Energetics
PPARs and Atherogenesis: Regulators of Gene Expression in Vascular Cells
Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis
Daniel Kelly Guest Editor
The heart has a tremendous capacity for ATP generation, allowing it to function as an efficient pump throughout the life of the organism. The adult myocardium uses either fatty acid or glucose oxidation as its main energy source. Under normal conditions, the adult heart derives most of its energy through oxidation of fatty acids in mitochondria. However, the myocardium has a remarkable ability to switch between carbohydrate and fat fuel sources so that ATP production is maintained at a constant rate in diverse physiological and dietary conditions. This fuel selection flexibility is important for normal cardiac function. Although cardiac energy conversion capacity and metabolic flux is modulated at many levels, an important mechanism of regulation occurs at the level of gene expression. The expression of genes involved in multiple energy transduction pathways is dynamically regulated in response to developmental, physiological, and pathophysiological cues. This review is focused on gene transcription pathways involved in short- and long-term regulation of myocardial energy metabolism. Much of our knowledge about cardiac metabolic regulation comes from studies focused on mitochondrial fatty acid oxidation. The genes involved in this key energy metabolic pathway are transcriptionally regulated by members of the nuclear receptor superfamily, specifically the fatty acid-activated peroxisome proliferator-activated receptors (PPARs) and the nuclear receptor coactivator, PPAR
coactivator-1
(PGC-1). The dynamic regulation of the cardiac PPAR/PGC-1 complex in accordance with physiological and pathophysiological states will be described.
Key Words: mitochondria • fatty acids • peroxisome proliferator-activated receptor • gene regulation • PPAR
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