Document Detail


Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries.
MedLine Citation:
PMID:  21525433     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Sergio de Frutos; Juan Manuel Ramiro Diaz; Carlos H Nitta; Mingma L Sherpa; Laura V Gonzalez Bosc
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Publication Detail:
Type:  Journal Article; Research Support, American Recovery and Reinvestment Act; Research Support, N.I.H., Extramural     Date:  2011-04-27
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  301     ISSN:  1522-1563     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2011 Aug 
Date Detail:
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    
Other Details:
Languages:  eng     Pagination:  C441-50     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Actins / metabolism
Active Transport, Cell Nucleus
Animals
Anoxia / genetics,  metabolism*
Calcineurin / antagonists & inhibitors,  metabolism
Calcium Channels, L-Type / drug effects,  metabolism
Calcium Signaling
Cells, Cultured
Chronic Disease
Cytoskeleton / metabolism
Disease Models, Animal
Endothelin-1 / antagonists & inhibitors,  genetics,  metabolism*
Genes, Reporter
Humans
Male
Membrane Transport Modulators / pharmacology
Mice
Mice, Inbred BALB C
Mice, Knockout
Muscle, Smooth, Vascular / drug effects,  metabolism*
Myocytes, Smooth Muscle / drug effects,  metabolism*
NFATC Transcription Factors / genetics,  metabolism*
Phosphorylation
Protein Kinase Inhibitors / pharmacology
Pulmonary Artery / drug effects,  metabolism*
RNA, Messenger / metabolism
Receptors, Endothelin / antagonists & inhibitors,  metabolism
Recombinant Fusion Proteins / metabolism
Time Factors
Transcriptional Activation
Transfection
Up-Regulation
rho GTP-Binding Proteins / metabolism
rho-Associated Kinases / antagonists & inhibitors,  metabolism
Grant Support
ID/Acronym/Agency:
R01 HL088151/HL/NHLBI NIH HHS; R01-HL-088151/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
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 2.7.11.1/rho-Associated Kinases; EC 3.1.3.16/Calcineurin; EC 3.6.5.2/RhoA protein, mouse; EC 3.6.5.2/rho GTP-Binding Proteins
Comments/Corrections

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