title: Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts.
abstract: 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.
authors.affiliation: Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Ferhana Y
authors.initials: FY
authors.lastname: Ali
authors.forename: Karine
authors.initials: K
authors.lastname: Egan
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D048068:PPAR-beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D011464:Epoprostenol; D008024:Ligands; D047495:PPAR gamma; D048068:PPAR-beta; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D013844:Thiazoles; C491910:Ptgir protein, mouse; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C427248:treprostinil