Clarendon Laboratory, Department of Physics, University of Oxford, Parks Road, Oxford OX1 3PU, U.K.
Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT Oxford, U.K.
Biochem Soc Trans. 2021 Aug 27;49(4):1855-1865. doi: 10.1042/BST20210538.
Pulmonary arterial hypertension (PAH) is a fatal disease of the cardiopulmonary system that lacks curative treatments. The main pathological event in PAH is elevated vascular resistance in the pulmonary circulation, caused by abnormal vasoconstriction and vascular remodelling. Ion channels are key determinants of vascular smooth muscle tone and homeostasis, and four PAH channelopathies (KCNK3, ABCC8, KCNA5, TRPC6) have been identified so far. However, the contribution of ion channels in other forms of PAH, which account for the majority of PAH patients, has been less well characterised. Here we reason that a variety of triggers of PAH (e.g. BMPR2 mutations, hypoxia, anorectic drugs) that impact channel function may contribute to the onset of the disease. We review the molecular mechanisms by which these 'extrinsic' factors converge on ion channels and provoke their dysregulation to promote the development of PAH. Ion channels of the pulmonary vasculature are therefore promising therapeutic targets because of the modulation they provide to both vasomotor tone and proliferation of arterial smooth muscle cells.
肺动脉高压（PAH）是一种心肺系统的致命疾病，缺乏治愈方法。PAH 的主要病理事件是肺循环中血管阻力升高，这是由异常的血管收缩和血管重塑引起的。离子通道是血管平滑肌张力和内稳态的关键决定因素，迄今为止已经确定了四种 PAH 通道病（KCNK3、ABCC8、KCNA5、TRPC6）。然而，在其他形式的 PAH 中，占大多数 PAH 患者的离子通道的贡献尚未得到很好的描述。在这里，我们认为 PAH 的多种触发因素（例如 BMPR2 突变、缺氧、厌食药）可能会影响离子通道的功能，从而导致疾病的发生。我们回顾了这些“外在”因素如何通过分子机制汇聚到离子通道并引发其失调，从而促进 PAH 的发展。因此，肺血管的离子通道是很有前途的治疗靶点，因为它们可以调节血管舒缩张力和动脉平滑肌细胞的增殖。
