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Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension

AIMS: We hypothesized that the ATP-sensitive K(+) channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K(+) channel Kir...

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Autores principales: Le Ribeuz, Hélène, Masson, Bastien, Dutheil, Mary, Boët, Angèle, Beauvais, Antoine, Sabourin, Jessica, De Montpreville, Vincent Thomas, Capuano, Véronique, Mercier, Olaf, Humbert, Marc, Montani, David, Antigny, Fabrice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871631/
https://www.ncbi.nlm.nih.gov/pubmed/36704469
http://dx.doi.org/10.3389/fcvm.2022.1066047
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author Le Ribeuz, Hélène
Masson, Bastien
Dutheil, Mary
Boët, Angèle
Beauvais, Antoine
Sabourin, Jessica
De Montpreville, Vincent Thomas
Capuano, Véronique
Mercier, Olaf
Humbert, Marc
Montani, David
Antigny, Fabrice
author_facet Le Ribeuz, Hélène
Masson, Bastien
Dutheil, Mary
Boët, Angèle
Beauvais, Antoine
Sabourin, Jessica
De Montpreville, Vincent Thomas
Capuano, Véronique
Mercier, Olaf
Humbert, Marc
Montani, David
Antigny, Fabrice
author_sort Le Ribeuz, Hélène
collection PubMed
description AIMS: We hypothesized that the ATP-sensitive K(+) channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K(+) channel Kir6.1. We investigated how the SUR2/Kir6.1 channel contributes to PAH pathogenesis and its potential as a therapeutic target in PAH. METHODS AND RESULTS: Using in vitro, ex vivo, and in vivo approaches, we analyzed the localization and expression of SUR2A, SUR2B, and Kir6.1 in the pulmonary vasculature of controls and patients with PAH as in experimental pulmonary hypertension (PH) rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of in vivo activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. We found that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat models. Organ bath studies showed that SUR2 activation by pinacidil induced relaxation of pulmonary arterial in rats and humans. In vitro experiments on human pulmonary arterial smooth muscle cells and endothelial cells (hPASMCs and hPAECs) in controls and PAH patients showed decreased cell proliferation and migration after SUR2 activation. We demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration by patch-clamp. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, in vivo pharmacological activation of SUR2 on MCT and Chronic-hypoxia (CH)-induced-PH rats showed improved PH. CONCLUSION: We showed that SUR2A, SUR2B, and Kir6.1 are presented in hPASMCs and hPAECs of controls and PAH patients. In vivo SUR2 activation reduced the MCT-induced and CH-induced PH phenotype, suggesting that SUR2 activation should be considered for treating PAH.
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spelling pubmed-98716312023-01-25 Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension Le Ribeuz, Hélène Masson, Bastien Dutheil, Mary Boët, Angèle Beauvais, Antoine Sabourin, Jessica De Montpreville, Vincent Thomas Capuano, Véronique Mercier, Olaf Humbert, Marc Montani, David Antigny, Fabrice Front Cardiovasc Med Cardiovascular Medicine AIMS: We hypothesized that the ATP-sensitive K(+) channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K(+) channel Kir6.1. We investigated how the SUR2/Kir6.1 channel contributes to PAH pathogenesis and its potential as a therapeutic target in PAH. METHODS AND RESULTS: Using in vitro, ex vivo, and in vivo approaches, we analyzed the localization and expression of SUR2A, SUR2B, and Kir6.1 in the pulmonary vasculature of controls and patients with PAH as in experimental pulmonary hypertension (PH) rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of in vivo activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. We found that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat models. Organ bath studies showed that SUR2 activation by pinacidil induced relaxation of pulmonary arterial in rats and humans. In vitro experiments on human pulmonary arterial smooth muscle cells and endothelial cells (hPASMCs and hPAECs) in controls and PAH patients showed decreased cell proliferation and migration after SUR2 activation. We demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration by patch-clamp. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, in vivo pharmacological activation of SUR2 on MCT and Chronic-hypoxia (CH)-induced-PH rats showed improved PH. CONCLUSION: We showed that SUR2A, SUR2B, and Kir6.1 are presented in hPASMCs and hPAECs of controls and PAH patients. In vivo SUR2 activation reduced the MCT-induced and CH-induced PH phenotype, suggesting that SUR2 activation should be considered for treating PAH. Frontiers Media S.A. 2023-01-10 /pmc/articles/PMC9871631/ /pubmed/36704469 http://dx.doi.org/10.3389/fcvm.2022.1066047 Text en Copyright © 2023 Le Ribeuz, Masson, Dutheil, Boët, Beauvais, Sabourin, De Montpreville, Capuano, Mercier, Humbert, Montani and Antigny. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Le Ribeuz, Hélène
Masson, Bastien
Dutheil, Mary
Boët, Angèle
Beauvais, Antoine
Sabourin, Jessica
De Montpreville, Vincent Thomas
Capuano, Véronique
Mercier, Olaf
Humbert, Marc
Montani, David
Antigny, Fabrice
Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension
title Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension
title_full Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension
title_fullStr Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension
title_full_unstemmed Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension
title_short Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension
title_sort involvement of sur2/kir6.1 channel in the physiopathology of pulmonary arterial hypertension
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871631/
https://www.ncbi.nlm.nih.gov/pubmed/36704469
http://dx.doi.org/10.3389/fcvm.2022.1066047
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