|Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries.|
|PMID: 21525433 Owner: NLM Status: MEDLINE|
|Chronic hypoxia (CH) activates the Ca(2+)-dependent transcription factor nuclear factor of activated T cells isoform c3 (NFATc3) in mouse pulmonary arteries. However, the mechanism of this response has not been explored. Since we have demonstrated that NFATc3 is required for CH-induced pulmonary arterial remodeling, establishing how CH activates NFATc3 is physiologically significant. The goal of this study was to test the hypothesis that endothelin-1 (ET-1) contributes to CH-induced NFATc3 activation. We propose that this mechanism requires increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca(2+) concentration ([Ca(2+)](i)) and stimulation of RhoA/Rho kinase (ROK), leading to calcineurin activation and actin cytoskeleton polymerization, respectively. We found that: 1) CH increases pulmonary arterial pre-pro-ET-1 mRNA expression and lung RhoA activity; 2) inhibition of ET receptors, calcineurin, L-type Ca(2+) channels, and ROK blunts CH-induced NFATc3 activation in isolated intrapulmonary arteries from NFAT-luciferase reporter mice; and 3) both ET-1-induced NFATc3 activation in isolated mouse pulmonary arteries ex vivo and ET-1-induced NFATc3-green fluorescence protein nuclear import in human PASMC depend on ROK and actin polymerization. This study suggests that CH increases ET-1 expression, thereby elevating PASMC [Ca(2+)](i) and RhoA/ROK activity. As previously demonstrated, elevated [Ca(2+)](i) is required to activate calcineurin, which dephosphorylates NFATc3, allowing its nuclear import. Here, we demonstrate that ROK increases actin polymerization, thus providing structural support for NFATc3 nuclear transport.|
|Sergio de Frutos; Juan Manuel Ramiro Diaz; Carlos H Nitta; Mingma L Sherpa; Laura V Gonzalez Bosc|
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|Type: Journal Article; Research Support, American Recovery and Reinvestment Act; Research Support, N.I.H., Extramural Date: 2011-04-27|
|Title: American journal of physiology. Cell physiology Volume: 301 ISSN: 1522-1563 ISO Abbreviation: Am. J. Physiol., Cell Physiol. Publication Date: 2011 Aug|
|Created Date: 2011-07-28 Completed Date: 2011-10-03 Revised Date: 2014-09-19|
Medline Journal Info:
|Nlm Unique ID: 100901225 Medline TA: Am J Physiol Cell Physiol Country: United States|
|Languages: eng Pagination: C441-50 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Active Transport, Cell Nucleus
Anoxia / genetics, metabolism*
Calcineurin / antagonists & inhibitors, metabolism
Calcium Channels, L-Type / drug effects, metabolism
Cytoskeleton / metabolism
Disease Models, Animal
Endothelin-1 / antagonists & inhibitors, genetics, metabolism*
Membrane Transport Modulators / pharmacology
Mice, Inbred BALB C
Muscle, Smooth, Vascular / drug effects, metabolism*
Myocytes, Smooth Muscle / drug effects, metabolism*
NFATC Transcription Factors / genetics, metabolism*
Protein Kinase Inhibitors / pharmacology
Pulmonary Artery / drug effects, metabolism*
RNA, Messenger / metabolism
Receptors, Endothelin / antagonists & inhibitors, metabolism
Recombinant Fusion Proteins / metabolism
rho GTP-Binding Proteins / metabolism
rho-Associated Kinases / antagonists & inhibitors, metabolism
|R01 HL088151/HL/NHLBI NIH HHS; R01-HL-088151/HL/NHLBI NIH HHS|
|0/Actins; 0/Calcium Channels, L-Type; 0/Endothelin-1; 0/Membrane Transport Modulators; 0/NFATC Transcription Factors; 0/Nfatc3 protein, mouse; 0/Protein Kinase Inhibitors; 0/RNA, Messenger; 0/Receptors, Endothelin; 0/Recombinant Fusion Proteins; EC 126.96.36.199/rho-Associated Kinases; EC 188.8.131.52/Calcineurin; EC 184.108.40.206/RhoA protein, mouse; EC 220.127.116.11/rho GTP-Binding Proteins|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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