电子T1针对TMEM RT老杂志文章16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1800965 DO 10.1183/13993003.00965-2018 VO 53 IS 6 A1 Papp, Rita A1 Nagaraj, Chandran A1 Zabini, Diana A1 Nagy, Bence M. A1 Lengyel, Miklós A1 Skofic Maurer, Davor A1 Sharma, Neha A1 Egemnazarov, Bakytbek A1 Kovacs, Gabor A1 Kwapiszewska, Grazyna A1 Marsh, Leigh M. A1 Hrzenjak, Andelko A1 Höfler, Gerald A1 Didiasova, Miroslava A1 Wygrecka, Malgorzata A1 Sievers, Laura K. A1 Szucs, Peter A1 Enyedi, Péter A1 Ghanim, Bahil A1 Klepetko, Walter A1 Olschewski, Horst A1 Olschewski, Andrea YR 2019 UL //www.qdcxjkg.com/content/53/6/1800965.abstract AB Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl− channel TMEM16A gene. We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH).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).In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl− current in PASMCs (n=9–10). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6–10). 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.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.TMEM16A plays a central role in the pathological mechanisms underlying the depolarisation, vasoconstriction and proliferation of PASMCs, contributing to the increased pulmonary vascular resistance in PAH, thus providing a novel target for PAH therapy http://ow.ly/3Rs330o3CUy