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Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic PAH

Rita Papp, Chandran Nagaraj, Diana Zabini, Bence M. Nagy, Miklós Lengyel, Davor Skofic Maurer, Neha Sharma, Bakytbek Egemnazarov, Gabor Kovacs, Grazyna Kwapiszewska, Leigh M. Marsh, Andelko Hrzenjak, Gerald Höfler, Miroslava Didiasova, Malgorzata Wygrecka, Laura Sievers, Peter Szucs, Péter Enyedi, Bahil Ghanim, Walter Klepetko, Horst Olschewski, Andrea Olschewski
European Respiratory Journal 2019; DOI: 10.1183/13993003.00965-2018
Rita Papp
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
*Contributed equally
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Chandran Nagaraj
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
*Contributed equally
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Diana Zabini
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Department of Physiology, Medical University of Graz, Graz, Austria
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Bence M. Nagy
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
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Miklós Lengyel
3Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
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Davor Skofic Maurer
2Department of Physiology, Medical University of Graz, Graz, Austria
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Neha Sharma
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
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Bakytbek Egemnazarov
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
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Gabor Kovacs
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Grazyna Kwapiszewska
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
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Leigh M. Marsh
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
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  • ORCID record for Leigh M. Marsh
Andelko Hrzenjak
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Gerald Höfler
5Department of Pathology, Medical University of Graz, Graz, Austria
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Miroslava Didiasova
6Department of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany
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Malgorzata Wygrecka
6Department of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany
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Laura Sievers
7Medical Clinic D, University Clinic of Münster, Münster, Germany
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Peter Szucs
8Department of Anatomy, Histology and Embriology, University of Debrecen, Debrecen, Hungary
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Péter Enyedi
3Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
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Bahil Ghanim
9Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
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Walter Klepetko
9Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
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Horst Olschewski
4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Andrea Olschewski
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Department of Physiology, Medical University of Graz, Graz, Austria
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  • For correspondence: andrea.olschewski@lvr.lbg.ac.at
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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.

This is a PDF-only article. Please click on the PDF link above to read it.

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Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic PAH
Rita Papp, Chandran Nagaraj, Diana Zabini, Bence M. Nagy, Miklós Lengyel, Davor Skofic Maurer, Neha Sharma, Bakytbek Egemnazarov, Gabor Kovacs, Grazyna Kwapiszewska, Leigh M. Marsh, Andelko Hrzenjak, Gerald Höfler, Miroslava Didiasova, Malgorzata Wygrecka, Laura Sievers, Peter Szucs, Péter Enyedi, Bahil Ghanim, Walter Klepetko, Horst Olschewski, Andrea Olschewski
European Respiratory Journal Jan 2019, 1800965; DOI: 10.1183/13993003.00965-2018

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Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic PAH
Rita Papp, Chandran Nagaraj, Diana Zabini, Bence M. Nagy, Miklós Lengyel, Davor Skofic Maurer, Neha Sharma, Bakytbek Egemnazarov, Gabor Kovacs, Grazyna Kwapiszewska, Leigh M. Marsh, Andelko Hrzenjak, Gerald Höfler, Miroslava Didiasova, Malgorzata Wygrecka, Laura Sievers, Peter Szucs, Péter Enyedi, Bahil Ghanim, Walter Klepetko, Horst Olschewski, Andrea Olschewski
European Respiratory Journal Jan 2019, 1800965; DOI: 10.1183/13993003.00965-2018
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