TY - JOUR T1 - Connexin 43 Is a Promising Target for Pulmonary Hypertension due To Hypoxemic Lung Disease JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00169-2019 SP - 1900169 AU - Claire Bouvard AU - Nafiisha Genet AU - Carole Phan AU - Baptiste Rode AU - Raphaël Thuillet AU - Ly Tu AU - Paul Robillard AU - Marilyne Campagnac AU - Raffaella Soleti AU - Eric Dumas De La Roque AU - Frédéric Delcambre AU - Laurent Cronier AU - Thibaud Parpaite AU - Elise Maurat AU - Patrick Berger AU - Jean-Pierre Savineau AU - Roger Marthan AU - Christophe Guignabert AU - Véronique Freund-Michel AU - Christelle Guibert Y1 - 2019/01/01 UR - http://erj.ersjournals.com/content/early/2019/11/26/13993003.00169-2019.abstract N2 - The mechanisms underlying pulmonary hypertension (PH) are complex and multifactorial and involve different cell types that are interconnected through gap junctional channels. Although connexin (Cx)-43 is the most abundant gap junction protein in heart and lungs and critically governs intercellular signalling communication, its contribution to PH remains unknown. The focus of the present study is thus to evaluate Cx43 as a potential new target in PH.Expressions of Cx37, Cx40, and Cx43 were studied in lung specimens from patients with idiopathic pulmonary arterial hypertension (iPAH) or PH associated to hypoxemic chronic lung diseases (CH-PH). Heterozygous Cx43 knockdown CD1 (Cx43+/−) and wild-type littermate (Cx43+/+) mice at 12 weeks of age were randomly divided into two groups, one of which was maintained in room air and the other exposed to hypoxia (10% O2) for 3 weeks. We evaluated pulmonary haemodynamics, remodelling processes in cardiac tissues and pulmonary arteries (PA), lung inflammation, and PA vasoreactivity.Cx43 levels were increased in PA from CH-PH patients, whereas Cx43 levels decreased in PA from iPAH patients. No difference in Cx37 or Cx40 was noted. Upon hypoxia treatment, the Cx43+/− mice were partially protected against chronic hypoxia-induced PH when compared to Cx43+/+ mice, with reduced pulmonary arterial muscularisation and inflammatory infiltration. Interestingly, the adaptive changes in cardiac remodelling in Cx43+/− mice were not affected. PA contraction to endothelin-1 was increased in Cx43+/- under normoxic and hypoxic conditions.Taken together, these results indicate that targeting Cx43 may have beneficial therapeutic effects in PH without affecting compensatory cardiac hypertrophy.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. bouvard has nothing to disclose.Conflict of interest: Dr. Genet has nothing to disclose.Conflict of interest: Carole PhanConflict of interest: Dr. Rode has nothing to disclose.Conflict of interest: Dr. Thuillet has nothing to disclose.Conflict of interest: Dr. TU has nothing to disclose.Conflict of interest: Dr. ROBILLARD has nothing to disclose.Conflict of interest: Dr. Campagnac has nothing to disclose.Conflict of interest: Dr. Soleti has nothing to disclose.Conflict of interest: Dr. Dumas De La Roque has nothing to disclose.Conflict of interest: Dr. Delcambre has nothing to disclose.Conflict of interest: Dr. CRONIER has nothing to disclose.Conflict of interest: Dr. Parpaite has nothing to disclose.Conflict of interest: Dr. Maurat has nothing to disclose.Conflict of interest: Dr. Berger reports grants from Nycomed, grants from Takeda, grants from Fondation du Souffle-Fonds de dotation Recherche en Santé Respiratoire, during the conduct of the study; grants and personal fees from Novartis, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Sanofi, personal fees from Menarinni, personal fees from TEVA, outside the submitted work.Conflict of interest: Dr. Savineau has nothing to disclose.Conflict of interest: Dr. Marthan has nothing to disclose.Conflict of interest: Dr. Guignabert has nothing to disclose.Conflict of interest: Dr. Freund-Michel has nothing to disclose.Conflict of interest: Dr. Guibert has nothing to disclose. ER -