Circulation Research. 2001;89:47-54
Published online before print June 21, 2001, doi: 10.1161/hh1301.092678
Published online before print June 21, 2001, doi: 10.1161/hh1301.092678
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© 2001 American Heart Association, Inc.
Cellular Biology |
Thrombin Activates the Hypoxia-Inducible Factor-1 Signaling Pathway in Vascular Smooth Muscle Cells
Role of the p22phox-Containing NADPH Oxidase
From the Institut für Kardiovaskuläre Physiologie (A.G., I.D., V.B.S.-K., R.P.B., R.B.), Klinikum der J.W. Goethe-Universität, Frankfurt/M.; Max-Planck-Institut für Molekulare Physiologie (U.B.-P.), Dortmund; and Institut für Biochemie und Molekulare Zellbiologie (U.R., T.K.), Universität Göttingen, Germany
Correspondence to Agnes Görlach, MD, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/M, Germany. E-mail A.Goerlach{at}em.uni-frankfurt.de
Abstract
Abstract—The
heterodimeric transcription factor hypoxia-inducible factor-1
(HIF-1) is activated under hypoxic conditions, resulting in the
upregulation of its target genes plasminogen
activator inhibitor-1 (PAI-1) and vascular
endothelial growth factor (VEGF). PAI-1 and VEGF are
also induced in response to vascular injury, which is characterized by
the activation of platelets and the coagulation cascade as well as
the generation of reactive oxygen species (ROS). However, it is not
known whether HIF-1 is also stimulated by thrombotic factors. We
investigated the role of thrombin, platelet-associated growth
factors, and ROS derived from the
p22phox-containing
NADPH oxidase in the activation of HIF-1 and the induction of its
target genes PAI-1 and VEGF in human vascular smooth muscle cells
(VSMCs). Thrombin, platelet-derived growth factor-AB (PDGF-AB), and
transforming growth factor-ß1
(TGF-ß1) upregulated HIF-1
protein in
cultured and native VSMCs. This response was accompanied by nuclear
accumulation of HIF-1 as well as by increased HIF-1 DNA-binding and
reporter gene activity. The thrombin-induced expression of HIF-1,
PAI-1, and VEGF was attenuated by antioxidant treatment as well as by
transfection of
p22phox
antisense oligonucleotides. Inhibition of p38
mitogen-activated protein kinase and
phosphatidylinositol-3-kinase significantly decreased thrombin-induced
HIF-1, PAI-1, and VEGF expression. These findings demonstrate that
the HIF-1 signaling pathway can be stimulated by thrombin and
platelet-associated growth factors and that a redox-sensitive cascade
activated by ROS derived from the
p22phox-containing
NADPH oxidase is crucially involved in this response.
Key Words: oxygen radicals • p22phox • platelets • vascular endothelial growth factor • plasminogen activator inhibitor-1
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E. L. Page, G. A. Robitaille, J. Pouyssegur, and D. E. Richard Induction of Hypoxia-inducible Factor-1alpha by Transcriptional and Translational Mechanisms J. Biol. Chem., December 6, 2002; 277(50): 48403 - 48409. [Abstract] [Full Text] [PDF]
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C. Schroedl, D. S. McClintock, G. R. S. Budinger, and N. S. Chandel Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L922 - L931. [Abstract] [Full Text] [PDF]
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 J. L. Evans, I. D. Goldfine, B. A. Maddux, and G. M. Grodsky Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes Endocr. Rev., October 1, 2002; 23(5): 599 - 622. [Abstract] [Full Text] [PDF]
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 Y. Guo, A. P. Mazar, J.-J. Lebrun, and S. A. Rabbani An Antiangiogenic Urokinase-derived Peptide Combined with Tamoxifen Decreases Tumor Growth and Metastasis in a Syngeneic Model of Breast Cancer Cancer Res., August 15, 2002; 62(16): 4678 - 4684. [Abstract] [Full Text] [PDF]
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S. Kaluz, M. Kaluzova, A. Chrastina, P. L. Olive, S. Pastorekova, J. Pastorek, M. I. Lerman, and E. J. Stanbridge Lowered Oxygen Tension Induces Expression of the Hypoxia Marker MN/Carbonic Anhydrase IX in the Absence of Hypoxia-inducible Factor 1{alpha} Stabilization: A Role for Phosphatidylinositol 3'-Kinase Cancer Res., August 1, 2002; 62(15): 4469 - 4477. [Abstract] [Full Text] [PDF]
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R. H. WENGER Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression FASEB J, August 1, 2002; 16(10): 1151 - 1162. [Abstract] [Full Text] [PDF]
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A. Barchowsky, N. V. Soucy, K. A. O'Hara, J. Hwa, T. L. Noreault, and A. S. Andrew A Novel Pathway for Nickel-induced Interleukin-8 Expression J. Biol. Chem., June 28, 2002; 277(27): 24225 - 24231. [Abstract] [Full Text] [PDF]
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A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon Phosphatidylinositol 3-Kinase/Akt Signaling Is Neither Required for Hypoxic Stabilization of HIF-1alpha nor Sufficient for HIF-1-dependent Target Gene Transcription J. Biol. Chem., April 19, 2002; 277(17): 15162 - 15170. [Abstract] [Full Text] [PDF]
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M. Alvarez-Tejado, A. Alfranca, J. Aragones, A. Vara, M. O. Landazuri, and L. del Peso Lack of Evidence for the Involvement of the Phosphoinositide 3-Kinase/Akt Pathway in the Activation of Hypoxia-inducible Factors by Low Oxygen Tension J. Biol. Chem., April 12, 2002; 277(16): 13508 - 13517. [Abstract] [Full Text] [PDF]
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H. P. Souza, X. Liu, A. Samouilov, P. Kuppusamy, F. R. M. Laurindo, and J. L. Zweier Quantitation of superoxide generation and substrate utilization by vascular NAD(P)H oxidase Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H466 - H474. [Abstract] [Full Text] [PDF]
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C. K. Sen, S. Khanna, M. Venojarvi, P. Trikha, E. C. Ellison, T. K. Hunt, and S. Roy Copper-induced vascular endothelial growth factor expression and wound healing Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1821 - H1827. [Abstract] [Full Text] [PDF]
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O. Herkert, I. Diebold, R. P. Brandes, J. Hess, R. Busse, and A. Gorlach NADPH Oxidase Mediates Tissue Factor-Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells Circulation, April 30, 2002; 105(17): 2030 - 2036. [Abstract] [Full Text] [PDF]
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