HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/L309    most recent 00091.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Whitman, E. M. Articles by Shimoda, L. A. Search for Related Content PubMed PubMed Citation Articles by Whitman, E. M. Articles by Shimoda, L. A.

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

Division of Pulmonary and Critical Care Medicine and Vascular Biology Program, Institute for Cell Engineering; and Departments of Medicine, Pediatrics, Oncology, and Radiation Oncology and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 8 March 2007 ; accepted in final form 28 November 2007

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 ([Ca²⁺]_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 [Ca²⁺]_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% CO₂) conditions. Hypoxia caused a decrease in expression of K_v1.5 and K_v2.1 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 K_v 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 K_v channel expression and rise in [Ca²⁺]_i during chronic hypoxia may be the result of HIF-1-dependent induction of ET-1.

hypoxia-inducible factor-1; pulmonary hypertension

This article has been cited by other articles:

				G. L. Semenza Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1 Physiology, April 1, 2009; 24(2): 97 - 106. [Abstract] [Full Text] [PDF]

				W. Lu, J. Wang, L. A. Shimoda, and J. T. Sylvester Differences in STIM1 and TRPC expression in proximal and distal pulmonary arterial smooth muscle are associated with differences in Ca2+ responses to hypoxia Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L104 - L113. [Abstract] [Full Text] [PDF]