Acid-sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension.
Acid-sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension.
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DOI：
10.1113/jp282231
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发表时间：
2021-11
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影响因子：
--
通讯作者：
Resta TC
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文献类型：
--
作者：
Jernigan NL;Naik JS;Resta TC
肺动脉高压的特征是持续的血管收缩和小动脉重构，这与肺动脉平滑肌细胞(PASMCs)静息膜电位(Em)的持续去极化有关。众所周知，这种去极化的潜在机制包括对K+通道的抑制；然而，是否其他离子通道参与了这种去极化还不清楚。我们先前报道PASMCs中存在酸敏感离子通道1(ASIC1)，它是一种非选择性阳离子通道，可同时传导Na+和Ca~(2+)，参与慢性低氧(CH)诱导的肺动脉高压的发生发展。因此，我们验证了ASIC1介导的Na+内流参与CH诱导的肺动脉高压后PASMC Em调节的假说。在大鼠和小鼠分离的加压小动脉上，我们使用锐尖电极细胞内记录显示，与对照动物相比，暴露于CH导致PASMC膜去极化，这与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，我们还发现全细胞非选择性阳离子通道(NSCC)电流增加，这是CH引起的PASMC持续的Em去极化所必需的。ASIC1的特异性抑制物Psalmooxin1和ASIC1的整体敲除(Asic1−/−)均可阻止CH诱导的Em去极化，并在很大程度上抑制全细胞的NSCC电流，而不影响全细胞的K+电流。我们的结果表明，包括抑制K+外流和增加Na+内流在内的多种因素共同介导了CH引起的PASMC去极化。此外，本研究还证实了ASIC1在CH诱导的肺动脉高压过程中对PASMCs内膜的调节中所起的新作用。
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 (Em) 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 that conducts both Na+ and Ca2+, 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 Em regulation following CH-induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show exposure to CH leads to PASMC membrane depolarization compared to 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 whole-cell non-selective cation channel (NSCC) currents are increased and essential to the persistent CH-induced Em depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout of ASIC1 (Asic1−/−) prevents CH-induced Em 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 Em in PASMCs during CH-induced pulmonary hypertension.