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Published ahead of print on October 20, 2005, doi:10.1165/rcmb.2005-0289OC
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2005-0289OCv1
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 242-246, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0289OC

Role of Prostacyclin versus Peroxisome Proliferator-Activated Receptor beta Receptors in Prostacyclin Sensing by Lung Fibroblasts

Ferhana Y. Ali, Karine Egan, Garret A. FitzGerald, Béatrice Desvergne, Walter Wahli, David Bishop-Bailey, Timothy D. Warner and Jane A. Mitchell

Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College; William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom; Center for Experimental Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Centre for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Correspondence and requests for reprints should be addressed to Jane A. Mitchell, Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK. E-mail: j.a.mitchell{at}ic.ac.uk

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 (PPARbeta). We examined the possibility that PPARbeta is a therapeutic target for the treatment of pulmonary hypertension. Using the newly approved (for pulmonary hypertension) prostacyclin mimetic treprostinil sodium, reporter gene assays for PPARbeta activation and measurement of lung fibroblast proliferation were analyzed. Treprostinil sodium was found to activate PPARbeta in reporter gene assays and to inhibit proliferation of human lung fibroblasts at concentrations consistent with an effect on PPARs but not on IP receptors. The effects of treprostinil sodium on human lung cell proliferation are mimicked by those of the highly selective PPARbeta ligand GW0742. There are no receptor antagonists for PPARbeta or for IP receptors, but by using lung fibroblasts cultured from mice lacking PPARbeta (PPARbeta–/–) or IP (IP–/–), we demonstrate that the antiproliferative effects of treprostinil sodium are mediated by PPARbeta and not IP in lung fibroblasts. These observations suggest that some of the local, longer-term benefits of treprostinil sodium on reducing the remodeling associated with pulmonary hypertension may be mediated by PPARbeta. This study is the first to identify PPARbeta as a potential therapeutic target for the treatment of pulmonary hypertension, which is important because orally active PPARbeta ligands have been developed for the treatment of dyslipidemia.

Key Words: fibroblast • nuclear receptors • PPARbeta • prostacyclin • pulmonary hypertension




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