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

Abstract

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.

• Authors: Lei Guo, Xiaobo Tang, Hua Tian, Ye Liu, Zhigang Wang, Hong Wu, Jing Wang, Sholi Guo, Daling Zhu
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 587 Issue 1-3 Pg. 187-95 (Jun 10 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18430420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxyeicosatetraenoic Acids
• Indicators and Reagents
• Kcnc4 protein, rat
• RNA, Messenger
• Shaw Potassium Channels
• 15-hydroxy-5,8,11,13-eicosatetraenoic acid
• Arachidonate 15-Lipoxygenase
• Calcium

Topics

• Animals
• Arachidonate 15-Lipoxygenase (metabolism)
• Blotting, Western
• Calcium (metabolism)
• Cell Separation
• Cells, Cultured
• Enzyme-Linked Immunosorbent Assay
• Hydroxyeicosatetraenoic Acids (metabolism, physiology)
• Hypoxia (metabolism)
• Indicators and Reagents
• Myocytes, Smooth Muscle (metabolism, physiology)
• Patch-Clamp Techniques
• Pulmonary Artery (cytology, metabolism, physiology)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Shaw Potassium Channels (biosynthesis, genetics)