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

E. Miles Whitman, Sarah Pisarcik, Trevor Luke, Michele Fallon, Jian Wang, J. T. Sylvester, Gregg L. Semenza, Larissa A. Shimoda

Research output: Contribution to journalArticlepeer-review

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 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 HIF-1-dependent increases in ET-1 lead to decreased Kv channel expression and subsequent elevation in [Ca 2+]i. Resting [Ca2+]i and K v channel expression were measured in cells exposed to control (18% O2, 5% CO2) and hypoxic (4% O2, 5% CO 2) conditions. Hypoxia caused a decrease in expression of K v1.5 and Kv2.1 and a significant increase in resting [Ca2+]i. The increase in [Ca2+]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 Kv channel expression and blunted the hypoxia-induced increase in [Ca2+] 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 Kv channel expression and rise in [Ca2+]i during chronic hypoxia may be the result of HIF-1-dependent induction of ET-1.

Original languageEnglish (US)
Pages (from-to)L309-L318
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume294
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Hypoxia-inducible factor-1
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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