Hypoxic stimulation of the stress-activated protein kinases in pulmonary artery fibroblasts.
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.
Scott
P H
PH
Department of Physiology and Pharmacology, University of Strathclyde, Royal College; Pulmonary Vascular Unit, Department of Respiratory Medicine, Western Infirmary, Glasgow G11, 6NT, UK.
Paul
A
A
Belham
C M
CM
Peacock
A J
AJ
Wadsworth
R M
RM
Gould
G W
GW
Welsh
D
D
Plevin
R
R
D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism*; D002417:Cattle; D002455:Cell Division; D002478:Cells, Cultured; D002852:Chromatography, Ion Exchange; D002908:Chronic Disease; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000201:enzymology*; D016193:G1 Phase; D006976:Hypertension, Pulmonary / Q000209:etiology; D000860:Hypoxia / Q000150:complications / Q000201:enzymology*; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D011651:Pulmonary Artery / Q000201:enzymology* / Q000473:pathology; D016196:S Phase; D012967:Sodium Dodecyl Sulfate; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen; D017346:Protein Serine-Threonine Kinases; D012967:Sodium Dodecyl Sulfate; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2