p38 MAP kinase isoform activity and cell cycle regulators in the proliferative response of pulmonary and systemic artery fibroblasts to acute hypoxia.
Many cardiopulmonary diseases are associated with pulmonary hypertension which adds significant co-morbidity. Pulmonary hypertension is due partly to vasoconstriction but sustained by pulmonary vascular remodelling. If pathological endpoints are to be reversed in patients with pulmonary hypertension, the processes by which vascular remodelling occur need to be determined. Hypoxia provides a good model of pulmonary hypertension. We have previously shown that chronic hypoxia results in increased proliferation of pulmonary artery fibroblasts and stimulation of the mitogen-activated protein kinase (MAPK) family of signalling enzymes. Under the same conditions systemic artery fibroblasts were unaffected. This differential response of pulmonary fibroblasts to hypoxia represents a model to investigate the processes of pulmonary artery remodelling. The current study showed that acute hypoxia was capable of causing enhanced proliferation in pulmonary but not systemic artery fibroblasts and was linked to increased activation of p38 MAP kinase. Second, we have now shown that it is alpha and gamma isoforms of p38 MAP kinase, which are responsible. Third we have shown a link between stimulation of p38 MAP kinase and HIF-1 proportional, variant induction. An increased understanding of the effects of hypoxia on remodelling and proliferation represents a critical step in identifying targets for the treatment of pulmonary hypertension.
Welsh
David J
DJ
Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, UK. david.welsh@bio.gla.ac.uk
Scott
Pamela H
PH
Peacock
Andrew J
AJ
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002453:Cell Cycle; D015687:Cell Hypoxia; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D048051:p38 Mitogen-Activated Protein Kinases