Am. J. Respir. Crit. Care Med., Volume 158, Number 3, September 1998, 958-962

Hypoxic Stimulation of the Stress-activated Protein Kinases in Pulmonary Artery Fibroblasts

PAMELA H. SCOTT, ANDREW PAUL, CHRISTOPHER M. BELHAM, ANDREW J. PEACOCK, ROGER M. WADSWORTH, GWYN W. GOULD, DAVID WELSH, and ROBIN PLEVIN

Department of Physiology and Pharmacology, University of Strathclyde, Royal College; Pulmonary Vascular Unit, Department of Respiratory Medicine, Western Infirmary; and Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom

Pulmonary hypertension in response to chronic hypoxia is invariably accompanied by remodeling of the pulmonary vessels but the mechanism by which hypoxia increases the replication of vascular cells is unknown. To investigate the hypothesis that hypoxia stimulates intracellular kinase cascades we measured the activity of "classic" mitogen-activated protein (MAP) kinase pathways and "stress- activated" MAP kinase pathways in bovine pulmonary artery fibroblasts subjected to hypoxia for up to 30 h. Hypoxia (1% O₂) stimulated strongly the stress-activated protein kinases, c-Jun NH₂-terminal kinase (JNK) and p38 MAP kinase. Two peaks of p38 MAP kinase activity at 6 and 24 h were associated with an increase in the activity of mitogen-activated protein kinase-activated protein (MAPKAP) kinase-2, the immediate downstream target of p38 MAP kinase. Furthermore, the second phase of p38 MAP kinase activity could be reversed if cells were reoxygenated after 12 h. These data suggest that hypoxic stimulation of pulmonary artery cells is mediated by activation of the stress-activated protein kinases.

This article has been cited by other articles:

				C. M. Carlin, A. J. Peacock, and D. J. Welsh Fluvastatin Inhibits Hypoxic Proliferation and p38 MAPK Activity in Pulmonary Artery Fibroblasts Am. J. Respir. Cell Mol. Biol., October 1, 2007; 37(4): 447 - 456. [Abstract] [Full Text] [PDF]

				H. Takahashi, N. Goto, Y. Kojima, Y. Tsuda, Y. Morio, M. Muramatsu, and Y. Fukuchi Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L450 - L458. [Abstract] [Full Text] [PDF]

				K. K. K. Sheares, T. K. Jeffery, L. Long, X. Yang, and N. W. Morrell Differential effects of TGF-{beta}1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, November 1, 2004; 287(5): L919 - L927. [Abstract] [Full Text] [PDF]

				K. R. Laderoute, J. M. Calaoagan, M. Knapp, and R. S. Johnson Glucose Utilization Is Essential for Hypoxia-Inducible Factor 1{alpha}-Dependent Phosphorylation of c-Jun Mol. Cell. Biol., May 15, 2004; 24(10): 4128 - 4137. [Abstract] [Full Text] [PDF]

				G. Hopfl, O. Ogunshola, and M. Gassmann HIFs and tumors--causes and consequences Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623. [Abstract] [Full Text] [PDF]

				M. R. Karamsetty, J. R. Klinger, and N. S. Hill Evidence for the role of p38 MAP kinase in hypoxia-induced pulmonary vasoconstriction Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L859 - L866. [Abstract] [Full Text] [PDF]

				S. Dorion, H. Lambert, and J. Landry Activation of the p38 Signaling Pathway by Heat Shock Involves the Dissociation of Glutathione S-Transferase Mu from Ask1 J. Biol. Chem., August 16, 2002; 277(34): 30792 - 30797. [Abstract] [Full Text] [PDF]

				L. Zhang, M. Bewick, and R. M. Lafrenie Role of Raf-1 and FAK in cell density-dependent regulation of integrin-dependent activation of MAP kinase Carcinogenesis, July 1, 2002; 23(7): 1251 - 1258. [Abstract] [Full Text] [PDF]

				A. Alfranca, M. D. Gutierrez, A. Vara, J. Aragones, F. Vidal, and M. O. Landazuri c-Jun and Hypoxia-Inducible Factor 1 Functionally Cooperate in Hypoxia-Induced Gene Transcription Mol. Cell. Biol., January 1, 2002; 22(1): 12 - 22. [Abstract] [Full Text] [PDF]

				D. J. WELSH, A. J. PEACOCK, M. MacLEAN, and M. HARNETT Chronic Hypoxia Induces Constitutive p38 Mitogen-activated Protein Kinase Activity That Correlates with Enhanced Cellular Proliferation in Fibroblasts from Rat Pulmonary But Not Systemic Arteries Am. J. Respir. Crit. Care Med., July 15, 2001; 164(2): 282 - 289. [Abstract] [Full Text] [PDF]

				D. C. Underwood, R. R. Osborn, S. Bochnowicz, E. F. Webb, D. J. Rieman, J. C. Lee, A. M. Romanic, J. L. Adams, D. W. P. Hay, and D. E. Griswold SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung Am J Physiol Lung Cell Mol Physiol, November 1, 2000; 279(5): L895 - L902. [Abstract] [Full Text] [PDF]

				J. Aragones, D. R. Jones, S. Martin, M. A. S. Juan, A. Alfranca, F. Vidal, A. Vara, I. Merida, and M. O. Landazuri Evidence for the Involvement of Diacylglycerol Kinase in the Activation of Hypoxia-inducible Transcription Factor 1 by Low Oxygen Tension J. Biol. Chem., March 23, 2001; 276(13): 10548 - 10555. [Abstract] [Full Text] [PDF]

				M. Das, D. M. Bouchey, M. J. Moore, D. C. Hopkins, R. A. Nemenoff, and K. R. Stenmark Hypoxia-induced Proliferative Response of Vascular Adventitial Fibroblasts Is Dependent on G Protein-mediated Activation of Mitogen-activated Protein Kinases J. Biol. Chem., May 4, 2001; 276(19): 15631 - 15640. [Abstract] [Full Text] [PDF]