Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
J Physiol. 2021 Nov;599(21):4749-4762. doi: 10.1113/JP282231. Epub 2021 Sep 25.
Pulmonary hypertension is characterized by sustained vasoconstriction and remodelling of the small pulmonary arteries, which is associated with persistent depolarization of the resting membrane potential (E ) of pulmonary arterial smooth muscle cells (PASMCs). It is well-known that the underlying mechanism of this depolarization includes inhibition of K channels; however, whether other ion channels contribute to this depolarization is unknown. We previously reported that acid-sensing ion channel 1 (ASIC1), a non-selective cation channel (NSCC) that conducts both Na and Ca , is present in PASMCs and contributes to the development of chronic hypoxia (CH)-induced pulmonary hypertension. Therefore, we tested the hypothesis that ASIC1-mediated Na influx contributes to PASMC E regulation following CH-induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show that exposure to CH leads to PASMC membrane depolarization compared with control animals, and this is independent of intraluminal pressure-induced depolarization. In addition to a decrease in PASMC whole-cell K currents following CH, we demonstrate that whole-cell NSCC currents are increased and essential to the persistent CH-induced E depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout of ASIC1 (Asic1 ) prevents CH-induced E depolarization and largely inhibits whole-cell NSCC currents, without affecting whole-cell K currents. Our results show a combination of factors, including inhibition of K efflux and augmented Na influx, mediate CH-induced PASMC depolarization. Furthermore, this study demonstrates a novel role for ASIC1 in the regulation of E in PASMCs during CH-induced pulmonary hypertension. KEY POINTS: In pulmonary hypertensive patients and animal models of pulmonary hypertension, the resting membrane potential (E ) of pulmonary arterial smooth muscle cells (PASMCs) is persistently depolarized. In addition to the well-established reduction of K conductance, we show that non-selective cation channel currents are increased and essential to the persistent E depolarization in PASMCs following chronic hypoxia (CH)-induced pulmonary hypertension. The current study provides novel evidence that acid-sensing ion channel 1 (ASIC1)-mediated Na influx induces membrane depolarization and regulates E in PASMCs following CH exposure. Although fairly quiescent under control conditions, our findings demonstrate a pathological function of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension.
肺动脉高压的特征是持续的小肺动脉收缩和重塑，这与肺动脉平滑肌细胞（PASMCs）的静息膜电位（E）持续去极化有关。众所周知，这种去极化的潜在机制包括抑制 K 通道；然而，其他离子通道是否有助于这种去极化尚不清楚。我们之前报道过，酸感应离子通道 1（ASIC1）是一种非选择性阳离子通道（NSCC），可传导 Na 和 Ca，存在于 PASMCs 中，并有助于慢性低氧（CH）诱导的肺动脉高压的发展。因此，我们测试了这样一个假设，即 CH 诱导的肺动脉高压后，ASIC1 介导的 Na 内流有助于 PASMC E 的调节。通过在大鼠和小鼠分离的加压小肺动脉中使用尖锐电极细胞内记录，我们发现与对照动物相比，CH 暴露导致 PASMC 膜去极化，并且这与管腔内压力诱导的去极化无关。除了 CH 后 PASMC 全细胞 K 电流减少外，我们还证明全细胞 NSCC 电流增加，对 PASMC 中持续的 CH 诱导的 E 去极化至关重要。ASIC1 的特异性抑制剂 psalmotoxin 1 和 ASIC1 的全局敲除（Asic1）都可以防止 CH 诱导的 E 去极化，并在很大程度上抑制全细胞 NSCC 电流，而不影响全细胞 K 电流。我们的结果显示，包括抑制 K 外流和增强的 Na 内流在内的多种因素共同介导 CH 诱导的 PASMC 去极化。此外，这项研究表明，ASIC1 在 CH 诱导的肺动脉高压期间调节 PASMC 中的 E 方面发挥了新的作用。关键点：在肺动脉高压患者和肺动脉高压动物模型中，肺动脉平滑肌细胞（PASMCs）的静息膜电位（E）持续去极化。除了已经确立的 K 电导减少外，我们还发现，非选择性阳离子通道电流增加，对 CH 诱导的肺动脉高压后 PASMC 中持续的 E 去极化至关重要。本研究提供了新的证据表明，酸感应离子通道 1（ASIC1）介导的 Na 内流诱导膜去极化，并调节 CH 暴露后 PASMC 中的 E。尽管在对照条件下相当静止，但我们的发现表明 ASIC1 在慢性低氧诱导的肺动脉高压发展中具有病理性作用。
