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J. Biol. Chem., Vol. 276, Issue 29, 27605-27612, July 20, 2001
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From the Center for Cardiovascular Research, Departments
of Hypoxia triggers a cascade of
cellular energy metabolic responses including a decrease in
mitochondrial oxidative flux. To characterize gene regulatory
mechanisms by which mitochondrial fatty acid oxidative capacity is
diminished in response to hypoxia, cardiac myocytes in culture were
exposed to long-chain fatty acids (LCFA) under normoxic or hypoxic
conditions. Hypoxia prevented the known LCFA-induced accumulation of
mRNA encoding muscle carnitine palmitoyltransferase I (M-CPT I), an
enzyme that catalyzes the rate-limiting step in mitochondrial fatty
acid oxidation (FAO). Under hypoxic conditions, myocytes exhibited
significant accumulation of intracellular neutral lipid consistent with
reduced CPT I activity and diminished FAO capacity. Transient
transfection experiments demonstrated that the hypoxia-mediated
blunting of M-CPT I gene expression occurs at the transcriptional
level, is localized to an LCFA/peroxisome proliferator-activated
receptor
Hypoxia Inhibits the Peroxisome Proliferator-activated
Receptor
/ Retinoid X Receptor Gene Regulatory Pathway in
Cardiac Myocytes
A MECHANISM FOR O2-DEPENDENT MODULATION OF
MITOCHONDRIAL FATTY ACID OXIDATION*
§¶,
, and**
Medicine, Pediatrics, and ** Molecular Biology & Pharmacology, Washington University School of Medicine,
St. Louis, Missouri 63110
(PPAR)/retinoid X receptor (RXR) response element
within the M-CPT I gene promoter, and is PPAR-dependent.
DNA-protein binding studies demonstrated that exposure to hypoxia
reduces PPAR/RXR binding activity. Immunoblotting studies
demonstrated that whereas hypoxia had no effect on nuclear levels of
PPAR protein, nuclear and cellular RXR levels were reduced.
Hypoxia also diminished the 9-cis-retinoic acid-mediated activation of a reporter containing an RXR homodimer response element.
These results demonstrate that hypoxia deactivates PPAR by reducing
the availability of its obligate partner RXR.
*
This work was supported in part by National Institutes of
Health Grants K08 HL03568 (to F. L.), RO1 DK45416, RO1 HL58493, P50
HL61006, P30 DK56341, and P30 DK52574.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Center for
Cardiovascular Research, Box 8086, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8908; Fax: 314-362-0186; E-mail: dkelly@imgate.wustl.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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