(Circulation. 2001;103:2387.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Novel Molecular Mechanism of Increased Myocardial Endothelin-1 Expression in the Failing Heart Involving the Transcriptional Factor Hypoxia-Inducible Factor-1
Induced for Impaired Myocardial Energy Metabolism
From the Cardiovascular Division (Y.K., T.M., K.Y., N.M., I.Y.), Department of Internal Medicine, Institute of Clinical Medicine, and Department of Pharmacology (K.G.), Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan.
Correspondence to Takashi Miyauchi, MD, PhD, Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. E-mail t-miyauc{at}md.tsukuba.ac.jp
Background—Hypoxia-inducible
factor (HIF)-1
is an important transcriptional factor that
activates the gene expression of glycolytic enzymes, which are
activated as compensation for impaired ß-oxidation of fatty
acid in the failing heart. We reported that cardiac endothelin (ET)-1
expression is markedly increased in heart failure. The mechanism,
however, is unknown. Because we found an HIF-1 binding site in the
5'-promoter region of the ET-1 gene, we hypothesized that HIF-1 is
involved in this mechanism.
Methods and Results—In
rat cardiomyocytes, luciferase assay and electrophoretic
mobility shift assay showed that HIF-1 transcriptionally
activates ET-1 gene expression by direct interaction with the
predicted DNA binding site in the 5'-promoter region. HIF-1 mRNA and
ET-1 mRNA in the failing heart increased during the aggravation of
heart failure in vivo in animal models, ie, rats with myocardial
infarction and hamsters with cardiomyopathy. In
cultured cardiomyocytes treated with a mitochondrial
inhibitor, HIF-1 mRNA and ET-1 mRNA were markedly
increased with activated glycolysis, and antisense
oligonucleotide for HIF-1 largely inhibited the
increased gene expression of ET-1.
Conclusions—The
present study revealed a novel molecular mechanism of upregulation
of myocardial ET-1 in heart failure, indicating that induction of
HIF-1 to stimulate glycolysis as an adaptation in heart failure
against impaired energy metabolism alternatively causes an
elevation of cardiac ET-1 gene expression as a
maladaptation.
Key Words: endothelin • heart failure • metabolism • genes
This article has been cited by other articles:
 |
|
 |
|
  S. de Frutos, L. Duling, D. Alo, T. Berry, O. Jackson-Weaver, M. Walker, N. Kanagy, and L. Gonzalez Bosc NFATc3 is required for intermittent hypoxia-induced hypertension Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2382 - H2390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yamashita, O. Ohneda, M. Nagano, M. Iemitsu, Y. Makino, H. Tanaka, T. Miyauchi, K. Goto, K. Ohneda, Y. Fujii-Kuriyama, et al. Abnormal Heart Development and Lung Remodeling in Mice Lacking the Hypoxia-Inducible Factor-Related Basic Helix-Loop-Helix PAS Protein NEPAS Mol. Cell. Biol., February 15, 2008; 28(4): 1285 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Mikaelian, D. Coluccio, K. T. Morgan, T. Johnson, A. L. Ryan, E. Rasmussen, R. Nicklaus, C. Kanwal, H. Hilton, K. Frank, et al. Temporal Gene Expression Profiling Indicates Early Up-regulation of Interleukin-6 in Isoproterenol-induced Myocardial Necrosis in Rat Toxicol Pathol, February 1, 2008; 36(2): 256 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Lourenco, R. Roncon-Albuquerque Jr., C. Bras-Silva, B. Faria, J. Wieland, T. Henriques-Coelho, J. Correia-Pinto, and A. F. Leite-Moreira Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1587 - H1594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kobayashi, H. Oku, M. Fukuhara, S. Kojima, A. Komori, M. Ichikawa, K. Katsumura, M. Kobayashi, T. Sugiyama, and T. Ikeda Endothelin-1 Enhances Glutamate-Induced Retinal Cell Death, Possibly through ETA Receptors Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4684 - 4690. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hocher, P. Kalk, T. Slowinski, M. Godes, A. Mach, S. Herzfeld, D. Wiesner, P. C. Arck, H.-H. Neumayer, and B. Nafz ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease J. Am. Soc. Nephrol., February 1, 2003; 14(2): 367 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Scheubel, M. Tostlebe, A. Simm, S. Rohrbach, R. Prondzinsky, F. N. Gellerich, R.-E. Silber, and J. Holtz Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2174 - 2181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Tham, J. Wang, F. Piehl, and G. Weber Upregulation of VEGF-A Without Angiogenesis in a Mouse Model of Dilated Cardiomyopathy Caused by Mitochondrial Dysfunction J. Histochem. Cytochem., July 1, 2002; 50(7): 935 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Kim, Y.-S. Cho, Y.-S. Chun, J.-W. Park, and M.-S. Kim Early Expression of Myocardial HIF-1{alpha} in Response to Mechanical Stresses: Regulation by Stretch-Activated Channels and the Phosphatidylinositol 3-Kinase Signaling Pathway Circ. Res., February 8, 2002; 90 (2): e25 - e33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Kline, Y.-J. Peng, D. J. Manalo, G. L. Semenza, and N. R. Prabhakar Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha PNAS, January 22, 2002; 99(2): 821 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Kim, Y.-S. Cho, Y.-S. Chun, J.-W. Park, and M.-S. Kim Early Expression of Myocardial HIF-1{alpha} in Response to Mechanical Stresses: Regulation by Stretch-Activated Channels and the Phosphatidylinositol 3-Kinase Signaling Pathway Circ. Res., February 8, 2002; 90 (2): e25 - e33. [Abstract] [Full Text] [PDF]
|
|