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

Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L309-18. doi: 10.1152/ajplung.00091.2007. Epub 2007 Dec 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Kv1.5 Potassium Channel / metabolism*
  • Male
  • Mice
  • Models, Biological
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Oligopeptides / pharmacology
  • Peptides, Cyclic / pharmacology
  • Perfusion
  • Piperidines / pharmacology
  • Pulmonary Artery / cytology*
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism*
  • Rats
  • Rats, Wistar
  • Shab Potassium Channels / genetics
  • Shab Potassium Channels / metabolism*

Substances

  • 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)