Abstract
Rationale Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl− channel TMEM16A gene.
Objective We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing PAH.
Methods and results We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary arterial smooth muscle cells (PASMC). In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl− current in PASMC (n=9–10). These cells were depolarised and could be repolarized by TMEM16A inhibitors or knock-down experiments (n=6–10). Inhibition/knock-down of TMEM16A reduced proliferation of IPAH-PASMC (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMC produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established PH.
Conclusion Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to achieve reverse remodelling in PAH.
Footnotes
This 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. Hrzenjak has nothing to disclose.
Conflict of interest: Dr. Olshewski has a patent File No. EP17169063.9: Modulation of the calcium-activated chloride channel including TMEM16A represent a novel therapy for pulmonary hypertension pending.
Conflict of interest: Dr. Didiasova has nothing to disclose.
Conflict of interest: Dr. Wygrecka has nothing to disclose.
Conflict of interest: Dr. Klepetko has nothing to disclose.
Conflict of interest: Dr. Ghanim has nothing to disclose.
Conflict of interest: Dr. Olschewski reports grants, personal fees and non-financial support from Actelion, grants, personal fees and nonfinancial support from Bayer, personal fees and non-financial support from GSK, personal fees from Novartis, personal fees from Astra Zeneca, grants, personal fees and non-financial support from Boehringer, personal fees and non-financial support from Chiesi, personal fees and non-financial support from Menarini, grants and personal fees from Roche, personal fees from Bellerophon, personal fees and non-financial support from TEVA, personal fees and non-financial support from MSD, personal fees and non-financial support from Ludwig Boltzmann Institute for Lung Vascular Research, outside the submitted work.
Conflict of interest: Dr. Egemnazarov has nothing to disclose.
Conflict of interest: Dr. Nagy reports In addition, Dr. Nagy has a patent (File No. EP17169063.9): Modulation of the calcium-activated chloride channel including TMEM16A represent a novel therapy for pulmonary hypertension pending.
Conflict of interest: Dr. Nagaraj reports In addition, Dr. Nagaraj has a patent (File No. EP17169063.9): Modulation of the calcium-activated chloride channel including TMEM16A represent a novel therapy for pulmonary hypertension pending.
Conflict of interest: Dr. Zabini has nothing to disclose.
Conflict of interest: Dr. Hoefler has nothing to disclose.
Conflict of interest: Dr. Kwapiszewska has nothing to disclose.
Conflict of interest: Dr. Marsh has nothing to disclose.
Conflict of interest: Dr. Schenk has nothing to disclose.
Conflict of interest: Dr. Papp reports In addition, Dr. Papp has a patent (File No. EP17169063.9): Modulation of the calcium-activated chloride channel including TMEM16A represent a novel therapy for pulmonary hypertension pending.
Conflict of interest: Dr. Szücs has nothing to disclose.
Conflict of interest: Dr. Kovacs reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from GSK, personal fees and non-financial support from MSD, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Novartis, personal fees and non-financial support from Chiesi, non-financial support from VitalAire, outside the submitted work.
Conflict of interest: Dr. Skofic Maurer has nothing to disclose.
Conflict of interest: Dr. Sharma has nothing to disclose.
Conflict of interest: Dr. Lengyel has nothing to disclose.
Conflict of interest: Dr. Enyedi has nothing to disclose.
Conflict of interest: Dr. Ghanim has nothing to disclose.
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