PMID- 18065659
OWN - NLM
STAT- MEDLINE
DCOM- 20080319
LR  - 20200930
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 294
IP  - 2
DP  - 2008 Feb
TI  - Endothelin-1 mediates hypoxia-induced inhibition of voltage-gated K+ channel 
      expression in pulmonary arterial myocytes.
PG  - L309-18
AB  - 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.
FAU - Whitman, E Miles
AU  - Whitman EM
AD  - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 5501 
      Hopkins Bayview Circle, Baltimore, MD 21224, USA.
FAU - Pisarcik, Sarah
AU  - Pisarcik S
FAU - Luke, Trevor
AU  - Luke T
FAU - Fallon, Michele
AU  - Fallon M
FAU - Wang, Jian
AU  - Wang J
FAU - Sylvester, J T
AU  - Sylvester JT
FAU - Semenza, Gregg L
AU  - Semenza GL
FAU - Shimoda, Larissa A
AU  - Shimoda LA
LA  - eng
GR  - HL 51912/HL/NHLBI NIH HHS/United States
GR  - HL 55338/HL/NHLBI NIH HHS/United States
GR  - HL 67191/HL/NHLBI NIH HHS/United States
GR  - HL 67919/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071207
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Endothelin-1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Kv1.5 Potassium Channel)
RN  - 0 (Oligopeptides)
RN  - 0 (Peptides, Cyclic)
RN  - 0 (Piperidines)
RN  - 0 (Shab Potassium Channels)
RN  - 44OLL8XEJ4 (BQ 788)
RN  - S2A8YZM151 (cyclo(Trp-Asp-Pro-Val-Leu))
SB  - IM
MH  - Animals
MH  - Calcium Signaling/drug effects
MH  - Endothelin-1/*metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Hypoxia/*metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Kv1.5 Potassium Channel/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Models, Biological
MH  - Myocytes, Smooth Muscle/drug effects/*metabolism
MH  - Oligopeptides/pharmacology
MH  - Peptides, Cyclic/pharmacology
MH  - Perfusion
MH  - Piperidines/pharmacology
MH  - Pulmonary Artery/*cytology/drug effects/*metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Shab Potassium Channels/genetics/*metabolism
EDAT- 2007/12/11 09:00
MHDA- 2008/03/20 09:00
CRDT- 2007/12/11 09:00
PHST- 2007/12/11 09:00 [pubmed]
PHST- 2008/03/20 09:00 [medline]
PHST- 2007/12/11 09:00 [entrez]
AID - 00091.2007 [pii]
AID - 10.1152/ajplung.00091.2007 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L309-18. doi: 
      10.1152/ajplung.00091.2007. Epub 2007 Dec 7.