title: 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.
abstract: Pulmonary hypertension occurs commonly in patients with chronic hypoxic lung disease and is characterized by the remodeling of the pulmonary artery walls. The molecular mechanisms underlying such remodeling are unknown but we have recently shown that the stress-activated (Jnk and p38) mitogen-activated protein (MAP) kinases are activated in pulmonary artery fibroblasts following acute hypoxia. We now show that Erk and p38 MAP kinases are constitutively activated in fibroblasts derived from the remodeled pulmonary, but not the systemic circulation from rats exposed to chronically hypoxic conditions. Moreover, we find that such fibroblasts show sustained enhanced proliferative capacities relative to pulmonary artery fibroblasts derived from normoxic rats or to aortic fibroblasts from either normoxic or hypoxic rats. Finally, abrogation of p38, but not Erk MAP kinase activity by use of specific inhibitors, prevents the enhanced proliferative capacity exhibited by pulmonary artery fibroblasts. Taken together, these data suggest that enhanced p38 MAP kinase activity provides a molecular mechanism to explain the proliferation of pulmonary artery fibroblasts required for remodeling of the pulmonary vasculature.
authors.affiliation: Scottish Pulmonary Vascular Unit and Department of Immunology, Western Infirmary, Glasgow G11 6NT, Scotland, United Kingdom.
authors.forename: D J
authors.initials: DJ
authors.lastname: Welsh
authors.forename: A J
authors.initials: AJ
authors.lastname: Peacock
authors.forename: M
authors.initials: M
authors.lastname: MacLean
authors.forename: M
authors.initials: M
authors.lastname: Harnett
mesh_terms: D000818:Animals; D002455:Cell Division; D002908:Chronic Disease; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology*; D000860:Hypoxia / Q000201:enzymology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011651:Pulmonary Artery; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases