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首页> 外文期刊>American Journal of Physiology >RhoA increases ASIC la plasma membrane localization and calcium influx in pulmonary arterial smooth muscle cells following chronic hypoxia
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RhoA increases ASIC la plasma membrane localization and calcium influx in pulmonary arterial smooth muscle cells following chronic hypoxia

机译：慢性缺氧后肺动脉平滑肌细胞中的AsiC La浆膜定位和钙流入量增加

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摘要

Increases in pulmonary arterial smooth muscle cell (PASMC) intracellular Ca~(2+) levels and enhanced RhoA/Rho kinase-dependent Ca~(2+) sensitization are key determinants of PASMC contraction, migration, and proliferation accompanying the development of hypoxic pulmonary hypertension. We previously showed that acid-sensing ion channel la (ASICla)-mediated Ca~(2+) entry in PASMC is an important constituent of the active vasocon-striction, vascular remodeling, and right ventricular hypertrophy associated with hypoxic pulmonary hypertension. However, the enhanced ASIC la-mediated store-operated Ca~(2+) entry in PASMC from pulmonary hypertensive animals is not dependent on an increase in ASICla protein expression, suggesting that chronic hypoxia (CH) stimulates ASICla function through other regulatory mechanism(s). RhoA is involved in ion channel trafficking, and levels of activated RhoA are increased following CH. Therefore, we hypothesize that activation of RhoA following CH increases ASICla-mediated Ca~(2+) entry by promoting ASICla plasma membrane localization. Consistent with our hypothesis, we found greater plasma membrane localization of ASICla following CH. Inhibition of RhoA decreased ASICla plasma membrane expression and largely diminished ASICla-mediated Ca~(2+) influx, whereas activation of RhoA had the opposite effect. A proximity ligation assay revealed that ASICla and RhoA colocalize in PASMC and that the activation state of RhoA modulates this interaction. Together, our findings show a novel interaction between RhoA and ASICla, such that activation of RhoA in PASMC, both pharmacologically and via CH, promotes ASICla plasma membrane localization and Ca~(2+) entry. In addition to enhanced RhoA-mediated Ca~(2+) sensitization following CH, RhoA can also activate a Ca~(2+) signal by facilitating ASICla plasma membrane localization and Ca~(2+) influx in pulmonary hypertension.
机译：肺动脉平滑肌细胞（PASMC）细胞内Ca〜（2+）水平的增加和增强的RHOO / RHO激酶依赖性CA〜（2+）致敏是缺氧肺部发育的脂肪收缩，迁移和增殖的关键决定因素高血压。我们以前表明，PASMC中的酸感测离子通道La（Asicla）介导的Ca〜（2+）进入是活性血管族划分，血管重塑和与缺氧肺动脉高压有关的右心室肥厚的重要组成部分。然而，来自肺高血压动物的增强型ASIC La介导的储存Ca〜（2+）进入来自肺高血压动物的蛋白质表达的增加，表明慢性缺氧（CH）通过其他调节机制刺激ASICLA功能（ s）。 RhoA参与离子通道运输，并且在CH中增加了活化的RHOA水平。因此，我们假设通过促进Asicla血浆膜定位，CH的激活增加了CH增加了Asicla介导的Ca〜（2+）进入。与我们的假设一致，我们发现ASICLA之后的血浆膜定位。抑制RhOA降低AsiCla血浆膜表达，大量减少Asicla介导的Ca〜（2+）流入，而RhOA的激活具有相反的效果。接近结扎测定显示，Asicla和rhOA在Pasmc中均匀化，并且RHOA的激活状态调节该相互作用。我们的研究结果表明了RhoA和Asicla之间的新相互作用，使得在药理学和通过CH的PASMC中激活RhOOA，促进了Asicla血浆膜定位和Ca〜（2+）进入。除了增强的RHOA介导的CA〜（2+）敏化之后，CH，RHOA还可以通过促进肺动脉高压中的ASICLA血浆膜定位和CA〜（2+）膨胀来激活CA〜（2+）信号。

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