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Tytuł:
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Interaction between PGI 2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients.
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Autorzy:
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Ozen G; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul 34116, Turkey.
Benyahia C; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Paris 13 University, 93430 Villetaneuse, France.
Amgoud Y; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Paris 13 University, 93430 Villetaneuse, France.
Patel J; Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
Abdelazeem H; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Paris 13 University, 93430 Villetaneuse, France.
Bouhadoun A; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Paris 13 University, 93430 Villetaneuse, France.
Yung S; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Paris 13 University, 93430 Villetaneuse, France.
Li F; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France.
Mahieddine Y; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France.
Silverstein AM; United Therapeutics Corporation, Research Triangle Park, NC 27709, USA.
Castier Y; Hôpital Bichat-Claude Bernard, AP-HP, 75018 Paris, France.
Cazes A; Hôpital Bichat-Claude Bernard, AP-HP, 75018 Paris, France.
Longrois D; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Hôpital Bichat-Claude Bernard, AP-HP, 75018 Paris, France.
Clapp LH; Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
Norel X; Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Paris 13 University, 93430 Villetaneuse, France. Electronic address: .
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Źródło:
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Prostaglandins & other lipid mediators [Prostaglandins Other Lipid Mediat] 2020 Feb; Vol. 146, pp. 106388. Date of Electronic Publication: 2019 Oct 28.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: New York : Elsevier Science, c1998-
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MeSH Terms:
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Signal Transduction*
Endothelin-1/*metabolism
Epoprostenol/*metabolism
Hypertension, Pulmonary/*metabolism
Muscle, Smooth, Vascular/*metabolism
Aged ; Endothelin-1/pharmacology ; Epoprostenol/pharmacology ; Female ; Humans ; Hypertension, Pulmonary/pathology ; Male ; Middle Aged ; Muscle, Smooth, Vascular/pathology ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; Pulmonary Veins/metabolism ; Pulmonary Veins/pathology ; Receptor, Endothelin A/metabolism ; Receptor, Endothelin B/metabolism
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Contributed Indexing:
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Keywords: Endothelin receptor antagonist; Human pulmonary artery; PGI(2)ET-1; Pulmonary hypertension
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Substance Nomenclature:
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0 (Endothelin-1)
0 (Receptor, Endothelin A)
0 (Receptor, Endothelin B)
DCR9Z582X0 (Epoprostenol)
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Entry Date(s):
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Date Created: 20191102 Date Completed: 20201112 Latest Revision: 20201112
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Update Code:
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20240104
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DOI:
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10.1016/j.prostaglandins.2019.106388
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PMID:
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31672620
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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.
(Copyright © 2019 Elsevier Inc. All rights reserved.)