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Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Ozen, G; Benyahia, C; Amgoud, Y; Patel, J; Abdelazeem, H; Bouhadoun, A; Yung, S; ... Norel, X; + view all (2020) Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients. Prostaglandins & Other Lipid Mediators , 146 , Article 106388. 10.1016/j.prostaglandins.2019.106388. Green open access

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Abstract

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_{2}) 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_{2} 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_{A} and ET_{B} 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_{2} 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_{A}/ET_{B} receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ET_{B} 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_{A} 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_{B} 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_{2} analogue and a selective ET_{A} receptor antagonist.

Type: Article
Title: Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.prostaglandins.2019.106388
Publisher version: https://doi.org/10.1016/j.prostaglandins.2019.1063...
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Endothelin receptor antagonist, Human pulmonary artery, PGI(2)ET-1, Pulmonary hypertension
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: https://discovery.ucl.ac.uk/id/eprint/10089891
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