Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension
Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension
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DOI：
10.1183/13993003.00965-2018
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发表时间：
2019-06-01
影响因子：
24.3
通讯作者：
Olschewski, Andrea
中科院分区：
文献类型：
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作者：
Papp, Rita;Nagaraj, Chandran;Olschewski, Andrea
我们对特发性肺动脉高压（IPAH）阴离子通道和转运蛋白的系统分析显示，Cl-通道TMEM 16 A基因显著上调。我们假设TMEM 16 A过表达可能代表了导致肺动脉高压（PAH）的分子途径中一种新的恶性循环。我们研究了健康供体肺（n=40）和IPAH受体肺（n=38）小肺动脉和肺动脉平滑肌细胞（PASMC）阴离子通道和转运蛋白基因的表达。在IPAH中，TMEM 16 A被强烈上调，并且膜片钳记录证实PASMC中Cl-电流增加（n=9-10）。这些细胞被去极化，并且可以通过TMEM 16 A抑制剂或敲低实验（n=6-10）再极化。TMEM 16 A的抑制/敲低降低了IPAH-PASMC的增殖（n=6）。相反，在健康供体PASMCs中TMEM 16 A的过表达产生IPAH样表型。慢性应用苯溴马隆在两个独立的动物模型显着降低右心室压力和逆转重建已建立的肺动脉高压，我们的研究结果表明，增加TMEM 16 A的表达和活性，包括一个重要的病理机制，血管收缩和肺动脉重建在PAH。抑制TMEM 16 A代表了逆转PAH重塑的新治疗方法。
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.