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首页> 外文期刊>American Journal of Physiology >Endothelin~(-1) mediates hypoxia-induced inhibition of voltage-gated K+ channel expression in pulmonary arterial myocytes
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Endothelin~(-1) mediates hypoxia-induced inhibition of voltage-gated K+ channel expression in pulmonary arterial myocytes

机译：内皮素〜（-1）介导低氧诱导的肺动脉心肌细胞电压门控性K +通道表达的抑制

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First published December 7, 2007; doi:10.1152/ajplung.00091.2007.-Prolonged exposure to decreased oxygen tension causes contraction and proliferation of pulmonary arterial smooth muscle cells (PASMCs) and pulmonary hypertension. Hypoxia-induced inhibition of voltage-gated K+ (Kv) channels may contribute to the development of pulmonary hypertension by increasing intracellular calcium concentration ([Ca~(2+)]i). The peptide endothelin~(-1) (ET~(-1)) has been implicated in the development of pulmonary hypertension and acutely decreases Kv channel activity. ET~(-1) also activates several transcription factors, although whether ET~(-1) alters Kv channel expression is unclear. The hypoxic induction of ET~(-1) is regulated by the transcription factor hypoxia-inducible factor~(-1) (HIF-1), which we demonstrated to regulate hypoxia-induced decreases in Kv channel activity. In this study, we tested the hypothesis that HEF~(-1)-dependent increases in ET~(-1) lead to decreased Kv channel expression and subsequent elevation in [Ca~(2+)]i. Resting [Ca~(2+)]i and Kv channel expression were measured in cells exposed to control (18% O2, 5% CO2) and hypoxic (4% O2, 5% CO2) conditions. Hypoxia caused a decrease in expression of KV1.5 and KV2.1 and a significant increase in resting [Ca~(2+)]i. The increase in [Ca~(2+)]i was reduced by nifedipine, an inhibitor of voltage-dependent calcium channels, and removal of extracellular calcium. Treatment with BQ-123, an ET~(-1) receptor inhibitor, prevented the hypoxia-induced de-crease in Kv channel expression and blunted the hypoxia-induced increase in [Ca~(2+)]i in PASMCs, whereas ET~(-1) mimicked the effects of hypoxia. Both hypoxia and overexpression of HIF~(-1) under nor-moxic conditions increased ET~(-1) expression. These results suggest that the inhibition of Kv channel expression and rise in [Ca~(2+)]i during chronic hypoxia may be the result of HEF~(-1)-dependent induction of ET~(-1).
机译：首次发布于2007年12月7日; doi：10.1152 / ajplung.00091.2007.-长时间暴露于降低的氧张力下会导致肺动脉平滑肌细胞（PASMC）收缩和增殖以及肺动脉高压。低氧诱导的电压门控性K +（Kv）通道抑制可能通过增加细胞内钙浓度（[Ca〜（2 +）] i）促进肺动脉高压的发展。肽内皮素（-1）（ET〜（-1））参与了肺动脉高压的发展，并严重降低了Kv通道的活性。尽管尚不清楚ET _（-1）是否改变Kv通道表达，但ET _（-1）还激活了一些转录因子。 ET〜（-1）的低氧诱导受转录因子低氧诱导因子〜（-1）（HIF-1）调控，我们证明了它可以调节低氧诱导的Kv通道活性降低。在这项研究中，我们测试了以下假设：依赖HEF〜（-1）的ET〜（-1）升高导致Kv通道表达降低，并随后导致[Ca〜（2 +）] i升高。在暴露于对照（18％O2、5％CO2）和低氧（4％O2、5％CO2）条件下的细胞中测量了静止的[Ca〜（2 +）] i和Kv通道表达。缺氧导致KV1.5和KV2.1的表达降低，而静止的[Ca〜（2 +）] i则显着增加。硝苯地平（一种电压依赖性钙通道的抑制剂）和细胞外钙的去除减少了[Ca〜（2 +）] i的增加。 ET〜（-1）受体抑制剂BQ-123的治疗阻止了低氧诱导的Kv通道表达减少，并抑制了低氧诱导的PASMCs [Ca〜（2 +）] i增加。 〜（-1）模拟了缺氧的影响。在缺氧条件下，缺氧和HIF〜（-1）的过表达均可增加ET〜（-1）的表达。这些结果提示慢性缺氧时Kv通道表达的抑制和[Ca〜（2 +）] i的升高可能是HEF〜（-1）依赖性ET〜（-1）诱导的结果。

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