p38 MAP kinase: essential role in hypoxia-mediated human pulmonary artery fibroblast proliferation.
Pulmonary arterial hypertension (PAH) is a disease that results in thickening of the vascular wall. Some of the most prominent changes are seen in the adventitia as a result of fibroblast proliferation and increased extracellular matrix deposition. Previous work from this laboratory using animal models has shown that pulmonary but not systemic artery fibroblasts proliferate to hypoxic exposure and that this response is dependent on activation of p38 mitogen-activated protein kinase (p38MAPK). In this study, we wished to determine whether human pulmonary artery fibroblasts (HPAFs) behaved similarly under conditions of acute hypoxic exposure (35 mmHg for 24 h). Fibroblast proliferation was assessed by [(3)H]thymidine uptake and protein assays performed using Western blotting techniques. HPAFs proliferated in response to acute hypoxic exposure, human systemic artery fibroblasts did not. This hypoxia-mediated proliferation was p38 MAPK dependent and could be blocked using a specific p38 MAPK inhibitor. Hypoxia-inducible factor-1 (HIF-1) expression was increased in hypoxic pulmonary but not systemic cells and could be partially abrogated with the p38 inhibitor. This work in man confirmed our previous findings in animals that significant differences exist between the pulmonary and systemic circulations in response to hypoxic exposure. This study highlights the importance of p38 MAPK and HIF-1 in hypoxia-mediated proliferation of pulmonary artery adventitial fibroblasts.
Mortimer
Heather J
HJ
Scottish Pulmonary Vascular Unit, Level 8, Western Infirmary, Glasgow, G11 6NT, Scotland, UK.
Peacock
Andrew J
AJ
Kirk
Alan
A
Welsh
David J
DJ
D015153:Blotting, Western; D015687:Cell Hypoxia; D049109:Cell Proliferation; D005347:Fibroblasts / Q000201:enzymology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D066298:In Vitro Techniques; D008323:Mammary Arteries / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D013936:Thymidine; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D048051:p38 Mitogen-Activated Protein Kinases; D013936:Thymidine