RT Journal Article
SR Electronic
T1 Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2000653
DO 10.1183/13993003.00653-2020
A1 Hélène Le Ribeuz
A1 Lucie To
A1 Maria-Rosa Ghigna
A1 Clémence Martin
A1 Chandran Nagaraj
A1 Elise Dreano
A1 Catherine Rucker-Martin
A1 Barbara Girerd
A1 Jérôme Bouliguan
A1 Christine Pechoux
A1 Mélanie Lambert
A1 Angèle Boet
A1 Justin Issard
A1 Olaf Mercier
A1 Konrad Hoetzenecker
A1 Boris Manoury
A1 Frédéric Becq
A1 Pierre-Régis Burgel
A1 Charles-Henry Cottart
A1 Andrea Olschewski
A1 Isabelle Sermet-Gaudelus
A1 Frédéric Perros
A1 Marc Humbert
A1 David Montani
A1 Fabrice Antigny
YR 2021
UL http://erj.ersjournals.com/content/early/2021/05/20/13993003.00653-2020.abstract
AB Introduction A reduction in pulmonary artery (PA) relaxation is a key event in pulmonary arterial hypertension (PAH) pathogenesis. CFTR dysfunction in airway epithelial cells plays a central role in cystic fibrosis (CF); CFTR is also expressed in PAs and has been shown to control endothelium-independent relaxation.Aim and objectives We aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.Methods and results RT-Q-PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in PAs from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myograph on human, pig and rat PAs, we demonstrated that CFTR activation induces PAs relaxation. CFTR-mediated PA relaxation was reduced in PAs from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularization. Pathologic assessment of lungs from patients with severe CF (F508del-CFTR) revealed severe PA remodeling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularization. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats.Conclusions CFTR expression is strongly decreased in PA smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces PA relaxation.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Le Ribeuz has nothing to disclose.Conflict of interest: Dr. TO has nothing to disclose.Conflict of interest: Dr. Rosa Ghigna has nothing to disclose.Conflict of interest: Dr. Martin has nothing to disclose.Conflict of interest: Dr. Nagaraj has nothing to disclose.Conflict of interest: Dr. Dreano has nothing to disclose.Conflict of interest: Dr. Rucker-Martin has nothing to disclose.Conflict of interest: Dr. Girerd has nothing to disclose.Conflict of interest: Dr. Bouligand has nothing to disclose.Conflict of interest: Dr. Péchoux has nothing to disclose.Conflict of interest: Dr. Lambert has nothing to disclose.Conflict of interest: Dr. Boët has nothing to disclose.Conflict of interest: Dr. Issard has nothing to disclose.Conflict of interest: Dr. Mercier has nothing to disclose.Conflict of interest: Dr. Hoetzenecker has nothing to disclose.Conflict of interest: Dr. Manoury has nothing to disclose.Conflict of interest: Dr. Becq has nothing to disclose.Conflict of interest: Dr. Burgel reports personal fees from Astra-Zeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GSK, personal fees from Novartis, personal fees from Pfizer, personal fees from Vertex, personal fees from Teva, from Zambon, from Mylan, outside the submitted work.Conflict of interest: Dr. Cottart reports grants from Vaincre La Mucoviscidose, grants from Fondation Maladies Rares, during the conduct of the study.Conflict of interest: Dr. Olschewski has nothing to disclose.Conflict of interest: Dr. Sermet-Gaudelus reports grants and other from Vertex therapeutics, other from Eloxx, other from Proteostasis therapeutics, outside the submitted work; .Conflict of interest: Dr. Perros has nothing to disclose.Conflict of interest: Dr. Humbert reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, personal fees from United Therapeutics, grants and personal fees from Acceleron, outside the submitted work.Conflict of interest: Dr. Montani reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, grants, personal fees and non-financial support from MSD, personal fees from Chiesi, personal fees from Boerhinger, non-financial support from Acceleron, outside the submitted work.Conflict of interest: Dr. Antigny has nothing to disclose.