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Published ahead of print on October 20, 2005, doi:10.1165/rcmb.2005-0289OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 2, February 2006, 242-246

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Submitted on July 26, 2005
Revised on September 21, 2005

Role of Prostacyclin Receptor Versus PPAR{beta} with Treprostinil Sodium on Lung Fibroblast Proliferation

Ferhana Y Ali1*, Karine Egan2, Garret A FitzGerald2, Beatrice Desvergne3, Walter Wahli3, David Bishop-Bailey4, Timothy D Warner4, and Jane A Mitchell5

1 Unit of Critical Care Medicine, Cardiothoracic Pharmacology, Imperial College, National Heart and Lung Institute, London, United Kingdom; Cardiac, Vascular and Inflammation, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom, 2 Centre for Experimental Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia, USA, 3 Centre for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, 4 Cardiac, Vascular and Inflammation, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom, 5 Unit of Critical Care Medicine, Cardiothoracic Pharmacology, Imperial College, National Heart and Lung Institute, London, United Kingdom

* To whom correspondence should be addressed. E-mail: ferhana.ali{at}imperial.ac.uk.

Rationale: Prostacyclin and its mimetics are used therapeutically for the treatment of pulmonary hypertension. These drugs act via cell surface prostacyclin receptors (IP receptors), however some of them can also activate the nuclear receptor peroxisome proliferator-activated receptor beta (PPAR{beta}). Objectives: We examined the possibility that PPAR{beta} is a therapeutic target for the treatment of pulmonary hypertension. Methods: Using the newly approved (for pulmonary hypertension) prostacyclin mimetic treprostinil sodium, reporter gene assays for PPAR{beta} activation and measurement of lung fibroblast proliferation were analysed. Results: Treprostinil sodium was found to activate PPAR{beta} in reporter gene assays and inhibits proliferation of human lung fibroblasts at concentrations consistent with an effect on PPARs, but not on IP receptors. Furthermore the effects of treprostinil sodium on human lung cell proliferation are mimicked by those of the highly selective PPAR{beta} ligand GW0742. There are no receptor antagonists for PPAR{beta} or for IP receptors, but by using lung fibroblasts cultured from mice lacking PPAR{beta} (PPAR{beta}-/-) or IP (IP-/-) we demonstrate that the anti-proliferative effects of treprostinil sodium are mediated by PPAR{beta} and not IP in lung fibroblasts. Conclusions: These observations suggest that some of the local, longer term benefits of treprostinil sodium on reducing the remodelling associated with pulmonary hypertension may be mediated by PPAR{beta}. This study is the first to identify PPAR{beta} as a potential therapeutic target for the treatment of pulmonary hypertension, which is particularly important since orally active PPAR{beta} ligands have already been developed for the treatment of dyslipidaemia.




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