From the Departamento de Farmacología y Toxicología. Facultad de Medicina, Universidad Complutense de Madrid, Spain (G.M.-P., B.B., M.C., S.E.-R., M.A.O., M.M., L.M., F.P.-V., A.C.).
Ciber Enfermedades Respiratorias (Ciberes), Spain (G.M.-P., B.B., M.C., S.E.-R., M.A.O., M.M., L.M., F.P.-V., A.C.).
Hypertension. 2020 Oct;76(4):1134-1146. doi: 10.1161/HYPERTENSIONAHA.120.15221. Epub 2020 Aug 24.
K channels play a fundamental role regulating membrane potential of pulmonary artery (PA) smooth muscle cells and their impairment is a common feature in pulmonary arterial hypertension (PAH). K voltage-gated channel subfamily Q () or Kv7 channels and their regulatory subunits subfamily E (KCNE) regulatory subunits are known to regulate vascular tone, but whether Kv7 channel function is impaired in PAH and how this can affect the rationale for targeting Kv7 channels in PAH remains unknown. Here, we have studied the role of Kv7/KCNE subunits in rat PA and their possible alteration in PAH. Using the patch-clamp technique, we found that the total K current is reduced in PA smooth muscle cells from pulmonary hypertension animals (SU5416 plus hypoxia) and Kv7 currents made a higher contribution to the net K current. Likewise, enhanced vascular responses to Kv7 channel modulators were found in pulmonary hypertension rats. Accordingly, KCNE4 subunit was highly upregulated in lungs from pulmonary hypertension animals and patients. Additionally, Kv7 channel activity was enhanced in the presence of Kv1.5 and TASK-1 channel inhibitors and this was associated with an increased KCNE4 membrane abundance. Compared with systemic arteries, PA showed a poor response to Kv7 channel modulators which was associated with reduced expression and membrane abundance of Kv7.4 and KCNE4. Our data indicate that Kv7 channel function is preserved and KCNE4 is upregulated in PAH. Therefore, compared with other downregulated channels, the contribution of Kv7 channels is increased in PAH resulting in an enhanced sensitivity to Kv7 channel modulators. This study provides insight into the potential usefulness of targeting Kv7 channels in PAH.
K 通道在调节肺动脉 (PA) 平滑肌细胞的膜电位方面发挥着基本作用，其功能障碍是肺动脉高压 (PAH) 的一个共同特征。已知 K 电压门控通道亚家族 Q (Kv7) 或 Kv7 通道及其调节亚基亚家族 E (KCNE) 调节亚基调节血管张力，但 Kv7 通道功能在 PAH 中是否受损以及这如何影响 Kv7 通道在 PAH 中的靶向作用的基本原理尚不清楚。在这里，我们研究了 Kv7/KCNE 亚基在大鼠 PA 中的作用及其在 PAH 中的可能改变。使用膜片钳技术，我们发现高血压动物 (SU5416 加缺氧) 的 PA 平滑肌细胞中的总 K 电流减少，而 Kv7 电流对净 K 电流的贡献更高。同样，在高血压大鼠中发现 Kv7 通道调节剂对血管的反应增强。相应地，KCNE4 亚基在高血压动物和患者的肺中高度上调。此外，在存在 Kv1.5 和 TASK-1 通道抑制剂的情况下，Kv7 通道活性增强，这与 KCNE4 膜丰度增加有关。与系统性动脉相比，PA 对 Kv7 通道调节剂的反应较差，这与 Kv7.4 和 KCNE4 的表达和膜丰度降低有关。我们的数据表明，Kv7 通道功能在 PAH 中得到保留，KCNE4 上调。因此，与其他下调的通道相比，Kv7 通道在 PAH 中的贡献增加，导致对 Kv7 通道调节剂的敏感性增强。这项研究为靶向 Kv7 通道在 PAH 中的潜在用途提供了深入了解。
