Subacute hypoxia suppresses Kv3.4 channel expression and whole-cell K⁺ currents through endogenous 15-hydroxyeicosatetraenoic acid in pulmonary arterial smooth muscle cells

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• 作者：Lei Guo ; Xiaobo Tang ; Hua Tian ; Ye Liu ; Zhigang Wang ; Hong Wu ; Jing Wang ; Sholi Guo ; Daling Zhu
• 关键词：Kv3.4 ; 15-lipoxygenase ; 15-hydroxyeicosatetraenoic acid ; Subacute hypoxia ; Pulmonary arterial smooth muscle cells
• 刊名：European Journal of Pharmacology
• 出版年：2008
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：10 June 2008
• 卷：587
• 期：1-3
• 页码：187-195
• 文件大小：1173 K

摘要

We have previously reported that subacute hypoxia activates lung 15-lipoxygenase (15-LOX), which catalyzes arachidonic acid to produce 15-HETE, leading to constriction of neonatal rabbit pulmonary arteries. Subacute hypoxia suppresses Kv3.4 channel expression and results in an inhibition of whole-cell K⁺ currents (I_K). Although the Kv channel inhibition is likely to be mediated through 15-HETE, direct evidence is still lacking. To reveal the role of the 15-LOX/15-HETE pathway in the hypoxia-induced down-regulation of Kv3.4 channel expression and inhibition of I_K, we performed studies using 15-LOX blockers, whole-cell patch-clamp, semi-quantitative PCR, ELISA and Western blot analysis. We found that Kv3.4 channel expression at the mRNA and protein levels was greatly up-regulated in pulmonary arterial smooth muscle cells after blockade of 15-LOX by CDC or NDGA. The 15-LOX blockade also partially restored I_K. In comparison, 15-HETE had a stronger effect than 12-HETE on the expression of Kv3.4 channels. 5-HETE had no noticeable effect on Kv3.4 channel expression. These data indicate that the 15-LOX pathway via its metabolite, 15-HETE, seems to play a role in the down-regulation of Kv3.4 expression and I_K inhibition after subacute hypoxia.