Abstract
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 the 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 with chronic hypoxaemic lung diseases (chronic hypoxia-induced pulmonary hypertension (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% oxygen) for 3 weeks. We evaluated pulmonary haemodynamics, remodelling processes in cardiac tissues and pulmonary arteries (PAs), lung inflammation and PA vasoreactivity.
Cx43 levels were increased in PAs from CH-PH patients and decreased in PAs from IPAH patients; however, no difference in Cx37 or Cx40 levels was noted. Upon hypoxia treatment, the Cx43+/− mice were partially protected against CH-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 due to endothelin-1 (ET-1) was increased in Cx43+/− mice 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.
Abstract
Connexin (Cx)-43, part of intercellular channels, is increased in patients with chronic hypoxia-induced pulmonary hypertension (CH-PH). It is crucial in lung inflammation and pulmonary artery remodelling in mice with CH-PH, suggesting Cx43 as a therapeutic option http://bit.ly/35zNkGm
Footnotes
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Support statement: This study was supported by the Fondation du Souffle and the Fonds de Dotation Recherche en Santé Respiratoire. B. Rode is funded by La Fondation Lefoulon Delalande. Funding information for this article has been deposited with the Crossref Funder Registry.
Conflict of interest: C. Bouvard has nothing to disclose.
Conflict of interest: N. Genet has nothing to disclose.
Conflict of interest: C. Phan has nothing to disclose.
Conflict of interest: B. Rode has nothing to disclose.
Conflict of interest: R. Thuillet has nothing to disclose.
Conflict of interest: L. Tu has nothing to disclose.
Conflict of interest: P. Robillard has nothing to disclose.
Conflict of interest: M. Campagnac has nothing to disclose.
Conflict of interest: R. Soleti has nothing to disclose.
Conflict of interest: E. Dumas De La Roque has nothing to disclose.
Conflict of interest: F. Delcambre has nothing to disclose.
Conflict of interest: L. Cronier has nothing to disclose.
Conflict of interest: T. Parpaite has nothing to disclose.
Conflict of interest: E. Maurat has nothing to disclose.
Conflict of interest: P. Berger reports grants from Nycomed, Takeda, Fondation du Souffle and Fonds de Dotation Recherche en Santé Respiratoire, during the conduct of the study; grants and personal fees for lectures, advisory board work and travel to meetings from Novartis, personal fees for lectures and non-financial (travel) support from Chiesi, grants and personal fees for advisory board work and lectures, as well as non-financial (travel) support from Boehringer Ingelheim, personal fees for advisory board work and lectures, as well as non-financial (travel) support from AstraZeneca and Sanofi, personal fees for advisory board work and lectures from Menarini, and personal fees for lectures from TEVA, outside the submitted work.
Conflict of interest: J-P. Savineau has nothing to disclose.
Conflict of interest: R. Marthan has nothing to disclose.
Conflict of interest: C. Guignabert has nothing to disclose.
Conflict of interest: V. Freund-Michel has nothing to disclose.
Conflict of interest: C. Guibert has nothing to disclose.
- Received January 24, 2019.
- Accepted November 27, 2019.
- Copyright ©ERS 2020