Interaction between PGI 2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

• Published in: Prostaglandins & other lipid mediators Vol. 146; p. 106388
• Main Authors: Ozen, Gulsev, Benyahia, Chabha, Amgoud, Yasmine, Patel, Jigisha, Abdelazeem, Heba, Bouhadoun, Amel, Yung, Sonia, Li, Fangfang, Mahieddine, Youcef, Silverstein, Adam M, Castier, Yves, Cazes, Aurélie, Longrois, Dan, Clapp, Lucie H, Norel, Xavier
• Format: Journal Article
• Language: English
• Published: United States 01.02.2020
• Subjects: Human pulmonary artery; PGIET-1; Endothelin receptor antagonist; Pulmonary hypertension
• ISSN: 1098-8823

Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI ) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ET and ET receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ET /ET receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ET receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ET receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control; -32±06% PH) than either agent alone. Of note, while the ET receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI analogue and a selective ET receptor antagonist.