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Low Dose Fluvastatin Reverses the Hypoxic Pulmonary Adventitial Fibroblast Phenotype in Experimental Pulmonary Hypertension.
MedLine Citation:
PMID:  22383583     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Rationale- Hypoxic pulmonary hypertension is a worldwide public health problem. Statins attenuate hypoxic pulmonary hypertension in animal models but the mechanism of action and applicability of these results to human treatment is not established. In hypoxic models, pulmonary artery fibroblast proliferation contributes substantially to pulmonary vascular remodelling. We have previously shown that acute hypoxic pulmonary adventitial fibroblast proliferation can be selectively inhibited by statins and p38 MAP kinase inhibitors. Here we utilised complementary chronic hypoxic and acute hypoxic co-culture models to obtain necessary pre-clinical information regarding the utility of fluvastastin for the treatment of chronic hypoxic pulmonary hypertension. Methods and results- The effects of fluvastastin, cholesterol pathway intermediates and related inhibitors on hypoxic adventitial fibroblast proliferation, p38 MAP kinase phosphorylation and pulmonary artery smooth muscle cell proliferation were determined, using complementary chronic hypoxic rat and acute hypoxic bovine cell models. Fluvastatin reversed the proliferative phenotypic switch in adventitial fibroblasts from chronic hypoxic animals. This effect was circulation specific and implicated a Rac1-p38 MAP kinase signalling pathway. Co-culture and conditioned media experiments also implicated this statin-sensitive signalling pathway in the release of PASMC mitogens by hypoxic pulmonary adventitial fibroblasts. Treprostinil, sildenafil and bosentan had no effect on the hypoxic fibroblast phenotype.Conclusions- Phenotypic changes (increased proliferation and mitogen release) in pulmonary artery fibroblasts in chronic hypoxia are dependent on a Rac1-p38 MAP kinase signalling pathway. Inhibition of these phenotypic changes with fluvastatin may be therapeutically relevant in high altitude residents and patients with hypoxic lung disease.
Authors:
Christopher M Carlin; Daniel F Celnick; Oleg Pak; Roger Wadsworth; Andrew J Peacock; David J Welsh
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-1
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  -     ISSN:  1535-4989     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, United Kingdom.
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