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We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH).<\/jats:p><jats:p>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 artery smooth muscle cells (PASMCs).<\/jats:p><jats:p>In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl<jats:sup>\u2212<\/jats:sup>current in PASMCs (n=9\u201310). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6\u201310). Inhibition\/knock-down of TMEM16A reduced the proliferation of IPAH-PASMCs (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established pulmonary hypertension.<\/jats:p><jats:p>Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying the vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in PAH.<\/jats:p>","DOI":"10.1183\/13993003.00965-2018","type":"journal-article","created":{"date-parts":[[2019,4,25]],"date-time":"2019-04-25T20:08:48Z","timestamp":1556222928000},"page":"1800965","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":79,"title":["Targeting TMEM16A to reverse vasoconstriction and remodelling in\u00a0idiopathic pulmonary arterial hypertension"],"prefix":"10.1183","volume":"53","author":[{"given":"Rita","family":"Papp","sequence":"first","affiliation":[]},{"given":"Chandran","family":"Nagaraj","sequence":"additional","affiliation":[]},{"given":"Diana","family":"Zabini","sequence":"additional","affiliation":[]},{"given":"Bence M.","family":"Nagy","sequence":"additional","affiliation":[]},{"given":"Mikl\u00f3s","family":"Lengyel","sequence":"additional","affiliation":[]},{"given":"Davor","family":"Skofic 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