Role of prostacyclin versus peroxisome proliferator-activated receptor β receptors in prostacyclin sensing by lung fibroblasts

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). We examined the possibility that PPAR beta 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 PPAR beta activation and measurement of lung fibroblast proliferation were analyzed. Treprostinil sodium was found to activate PPAR beta 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 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 antiproliferative effects of treprostinil sodium are mediated by PPAR beta 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 PPAR beta. This study is the first to identify PPAR beta as a potential therapeutic target for the treatment of pulmonary hypertension, which is important because orally active PPAR beta ligands have been developed for the treatment of dyslipidemia.