Submitted on September 8, 2008
Revised on January 30, 2009
Accepted on January 30, 2009
Inhibition of p38 MAP Kinase Reverses Hypoxia Induced Pulmonary Artery Endothelial Dysfunction
Roshan P Weerackody1, David J Welsh1*, Roger M Wadsworth2, and Andrew J Peacock1
1 Western Infirmary
2 University of Strathclyde
* To whom correspondence should be addressed. E-mail: david.welsh{at}bio.gla.ac.uk.
Background: Hypoxia induced endothelial dysfunction plays a crucial role in the pathogenesis of hypoxic pulmonary hypertension. p38 MAP kinase expression is increased in the pulmonary artery following hypoxic exposure. Recent evidence suggest that increased p38 MAP kinase activity is associated with endothelial dysfunction. However, the role of p38 MAP kinase activation in pulmonary artery endothelial dysfunction is not known. Methods and results: Sprague-Dawley rats were exposed to 2 weeks hypobaric hypoxia which resulted in development of pulmonary hypertension and vascular remodelling. Endothelial dependent relaxation of intra-pulmonary vessels from hypoxic animals was impaired due to reduced NO generation. This was despite increased eNOS immunostaining and protein expression. Hypoxia exposure increased superoxide generation and p38 MAP kinase expression. Inhibition of p38 MAP kinase restored endothelial dependent relaxation, increased bio-available NO and reduced superoxide production. Conclusion: Pharmacological inhibition of p38 MAP kinase was effective in increasing NO generation, reducing superoxide burden and restoring hypoxia induced endothelial dysfunction in rats with hypoxia-induced pulmonary hypertension. p38 MAP kinase may be a novel target for treatment of pulmonary hypertension.
