Downregulation of PGI₂ pathway in Pulmonary Hypertension Group-III patients

Pulmonary hypertension (PH) is a progressive and life-threating lung disorder characterized by elevated pulmonary artery pressure and vascular remodeling. PH is classified into five groups, and one of the most common and lethal forms, PH Group-III is defined as PH due to lung diseases and/or hypoxia. Due to the lack of studies in this group, PH-specific drug therapies including prostacyclin (PGI₂) analogues have not been approved or recommended for use in these patients. PGI₂ is synthesized by the PGI₂ synthase (PGIS) enzyme, and its production is determined by measuring its stable metabolite, 6-keto-PGF_1α. An impaired PGI₂ pathway has been observed in PH animal models and in PH Group-I patients; however, there are contradictory results. The aim of this study is to determine whether PH Group-III is associated with altered expression of PGIS and production of PGI₂ in humans. To explore this hypothesis, we measured PGIS expression (by western blot) and PGI₂ production (by ELISA) in a large variety of preparations from the pulmonary circulation including human pulmonary artery, pulmonary vein, distal lung tissue, pulmonary artery smooth muscle cells (hPASMC), and bronchi in PH Group-III (n = 35) and control patients (n = 32). Our results showed decreased PGIS expression and/or 6-keto-PGF_1α levels in human pulmonary artery, hPASMC, and distal lung tissue derived from PH Group-III patients. Moreover, the production of 6-keto-PGF_1α from hPASMC positively correlated with PGIS expression and was inversely correlated with mean pulmonary artery pressure. On the other hand, PH Group-III pulmonary veins and bronchi did not show altered PGI₂ production compared to controls. The deficit in PGIS expression and/or PGI₂ production observed in pulmonary artery and distal lung tissue in PH Group-III patients may have important implications in the pathogenesis and treatment of PH Group-III.