| Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries. | |
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MedLine Citation:
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PMID: 21525433 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sergio de Frutos; Juan Manuel Ramiro Diaz; Carlos H Nitta; Mingma L Sherpa; Laura V Gonzalez Bosc |
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Publication Detail:
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Type: Journal Article; Research Support, American Recovery and Reinvestment Act; Research Support, N.I.H., Extramural Date: 2011-04-27 |
Journal Detail:
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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:
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Created Date: 2011-07-28 Completed Date: 2011-10-03 Revised Date: 2012-09-25 |
Medline Journal Info:
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Nlm Unique ID: 100901225 Medline TA: Am J Physiol Cell Physiol Country: United States |
Other Details:
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Languages: eng Pagination: C441-50 Citation Subset: IM |
Affiliation:
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Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM, 87131, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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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:
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R01 HL088151-05/HL/NHLBI NIH HHS; R01-HL-088151/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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