Document Detail


Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production.
MedLine Citation:
PMID:  22842492     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Increased pulmonary artery endothelial cell (PAEC) endothelium-dependent nitric oxide synthase (eNOS) activity mediates perinatal pulmonary vasodilation. Compromised eNOS activity is central to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN). Voltage-derived anion channel (VDAC)-1 was recently demonstrated to bind eNOS in the systemic circulation. We hypothesized that VDAC isoforms modulate eNOS activity in the pulmonary circulation, and that decreased VDAC expression contributes to PPHN. In PAECs derived from an ovine model of PPHN: (1) there is eNOS activity, but not expression; and (2) VDAC1 and -2 proteins are decreased. Immunocytochemistry, coimmunoprecipitation, and in situ proximity ligation assays in human PAECs (hPAECs) demonstrate binding between eNOS and both VDAC1 and -2, which increased upon stimulation with NO agonists. The ability of agonists to increase the eNOS/VDAC interaction was significantly blunted in hypertensive, compared with normotensive, ovine PAECs. Depletion of VDAC2, but not VDAC1, blocked the agonist-induced increase in eNOS activity in hPAECs. Overexpression of VDAC2 in hypertensive PAECs increased eNOS activity. Binding of VDAC2 enhances eNOS activity in the pulmonary circulation, and diminished VDAC2 constrains eNOS in PAECs derived from fetal lambs with chronic intrauterine pulmonary hypertension. We speculate that decreases in VDAC2 may contribute to the limited eNOS activity that characterizes pulmonary hypertension.
Authors:
Cristina M Alvira; Anita Umesh; Cristiana Husted; Lihua Ying; Yanli Hou; Shu-Chen Lyu; Jeffrey Nowak; David N Cornfield
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-27
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  47     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-05     Completed Date:  2013-01-17     Revised Date:  2014-03-21    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  669-78     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcimycin / pharmacology
Cells, Cultured
Endothelial Cells / enzymology*,  metabolism,  pathology
Endothelium, Vascular / pathology
Gene Expression
Histamine / physiology
Humans
Infant, Newborn
Nitric Oxide Synthase Type III / antagonists & inhibitors,  genetics,  metabolism*
Persistent Fetal Circulation Syndrome / enzymology,  metabolism,  pathology
Protein Binding
Protein Interaction Mapping
Pulmonary Artery / pathology*
Sheep
Voltage-Dependent Anion Channel 1 / genetics,  metabolism
Voltage-Dependent Anion Channel 2 / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
1P30HL101315-01/HL/NHLBI NIH HHS; R01 HL070628/HL/NHLBI NIH HHS; R01-HL-60784/HL/NHLBI NIH HHS; R01-HL-70628/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/VDAC1 protein, human; 0/VDAC2 protein, human; 0/Voltage-Dependent Anion Channel 2; 37H9VM9WZL/Calcimycin; 820484N8I3/Histamine; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.6.-/Voltage-Dependent Anion Channel 1
Comments/Corrections

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