Supplemental Digital Content is available in the text. 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 (KCNQ1-5) 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.

中文翻译：

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揭示 Kv7 通道对肺动脉高压肺血管张力的贡献

文本中提供了补充数字内容。K+ 通道在调节肺动脉 (PA) 平滑肌细胞的膜电位方面发挥着重要作用，其损伤是肺动脉高压 (PAH) 的共同特征。已知 K+ 电压门控通道亚家族 Q (KCNQ1-5) 或 Kv7 通道及其调节亚基亚家族 E (KCNE) 调节亚基可调节血管张力，但 Kv7 通道功能是否在 PAH 中受损以及这如何影响靶向 PAH 中的 Kv7 通道仍然未知。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，我们发现肺动脉高压动物（SU5416 加缺氧）的 PA 平滑肌细胞中总 K+ 电流降低，Kv7 电流对净 K+ 电流的贡献更大。同样，在肺动脉高压大鼠中发现对 Kv7 通道调节剂的血管反应增强。因此，KCNE4 亚基在肺动脉高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。与全身动脉相比，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 通道功能得以保留，KCNE4 在 PAH 中上调。所以，与其他下调通道相比，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。这项研究提供了对 PAH 中靶向 Kv7 通道的潜在用途的深入了解。