1. Endothelin-1 mediates hypoxia-induced inhibition of voltage-gated K+ channel expression in pulmonary arterial myocytes.
- Author
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Whitman EM, Pisarcik S, Luke T, Fallon M, Wang J, Sylvester JT, Semenza GL, and Shimoda LA
- Subjects
- Animals, Calcium Signaling drug effects, Gene Expression Regulation drug effects, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Kv1.5 Potassium Channel genetics, Male, Mice, Models, Biological, Myocytes, Smooth Muscle drug effects, Oligopeptides pharmacology, Peptides, Cyclic pharmacology, Perfusion, Piperidines pharmacology, Pulmonary Artery drug effects, Rats, Rats, Wistar, Shab Potassium Channels genetics, Endothelin-1 metabolism, Hypoxia metabolism, Kv1.5 Potassium Channel metabolism, Myocytes, Smooth Muscle metabolism, Pulmonary Artery cytology, Pulmonary Artery metabolism, Shab Potassium Channels metabolism
- 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.
- Published
- 2008
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