Endothelin-1 mediates hypoxia-induced inhibition of voltage-gated K+ channel expression in pulmonary arterial myocytes.

Abstract

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(+) (K(v)) 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 K(v) channel activity. ET-1 also activates several transcription factors, although whether ET-1 alters K(V) 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 K(V) channel activity. In this study, we tested the hypothesis that HIF-1-dependent increases in ET-1 lead to decreased K(v) channel expression and subsequent elevation in [Ca(2+)](i). Resting [Ca(2+)](i) and K(v) channel expression were measured in cells exposed to control (18% O(2), 5% CO(2)) and hypoxic (4% O(2), 5% CO(2)) conditions. Hypoxia caused a decrease in expression of K(v)1.5 and K(v)2.1 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 decrease in K(v) 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 normoxic conditions increased ET-1 expression. These results suggest that the inhibition of K(v) channel expression and rise in [Ca(2+)](i) during chronic hypoxia may be the result of HIF-1-dependent induction of ET-1.

• Authors: E Miles Whitman, Sarah Pisarcik, Trevor Luke, Michele Fallon, Jian Wang, J T Sylvester, Gregg L Semenza, Larissa A Shimoda
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 294 Issue 2 Pg. L309-18 (Feb 2008) ISSN: 1040-0605 [Print] United States
• PMID: 18065659 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Kv1.5 Potassium Channel
• Oligopeptides
• Peptides, Cyclic
• Piperidines
• Shab Potassium Channels
• BQ 788
• cyclo(Trp-Asp-Pro-Val-Leu)

Topics

• Animals
• Calcium Signaling (drug effects)
• Endothelin-1 (metabolism)
• Gene Expression Regulation (drug effects)
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Kv1.5 Potassium Channel (genetics, metabolism)
• Male
• Mice
• Models, Biological
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Oligopeptides (pharmacology)
• Peptides, Cyclic (pharmacology)
• Perfusion
• Piperidines (pharmacology)
• Pulmonary Artery (cytology, drug effects, metabolism)
• Rats
• Rats, Wistar
• Shab Potassium Channels (genetics, metabolism)