Role of Prostacyclin versus Peroxisome Proliferator-Activated Receptor β 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.

Adenoassociated Virus–Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats

“…18 Interestingly, another PGI 2 analogue, treprostinil, also inhibits the proliferation of human and mouse primary lung fibroblasts through the activation of a peroxisome proliferator-activated receptor-␤/␦ when used in equivalent doses. 19 These observations suggest that high levels of PGI 2 may attenuate PA remodeling in vivo through antiproliferative effects. Consistent with previous studies, we demonstrated that high levels of endogenous PGI 2 successfully attenuated medial hypertrophy of the PA. 3,4,6 To discover new drug targets, the roles of peroxisome proliferator-activated receptors and high-level PGI 2 in PAH therapy should be determined, because peroxisome proliferator-activated receptors are associated with many inflammatory and proliferative disorders, including PAH.…”

Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension

“…Apart from this, prostacyclins inhibit the production of various cytokines and inflammatory mediators and suppress neutrophil adhesion [8,43]. It has been shown that treprostinil mediates antiproliferative mechanisms of resident lung fibroblasts [44]. Another prostacyclin analogue, iloprost was shown to have a beneficial effect in asthma [45].…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…In marked contrast, G i -coupled IP receptors were found exclusively in human erythroleukemia HEL cells with respect to STAT1 and STAT3 phosphorylation (Lo et al, 2006) and rat medullary thick ascending limb cells . Finally, but beyond the intended scope of this review, there are reports claiming that prostacyclin interacts with peroxisome proliferator-activated receptors to exert a portion of its activities (Lim and Dey, 2002;Ali et al, 2006).…”

“…Finally, IP(Ϫ/Ϫ) mice were used to distinguish some actions of PGI analogs on IP and PPAR␤. Ali et al (2006) used lung fibroblasts from IP(Ϫ/Ϫ) mice and those from PPAR␤(Ϫ/Ϫ) mice, examined inhibitory effects of treprostinil on their proliferation, and found that this activity was lost in PPAR␤(Ϫ/Ϫ) cells but not in IP(Ϫ/Ϫ) cells.…”