Document Detail


Genetic modifiers of cardiovascular phenotype caused by elastin haploinsufficiency act by extrinsic noncomplementation.
MedLine Citation:
PMID:  22049077     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Elastin haploinsufficiency causes the cardiovascular complications associated with Williams-Beuren syndrome and isolated supravalvular aortic stenosis. Significant variability exists in the vascular pathology in these individuals. Using the Eln(+/-) mouse, we sought to identify the source of this variability. Following outcrossing of C57Bl/6J Eln(+/-), two backgrounds were identified whose cardiovascular parameters deviated significantly from the parental strain. F1 progeny of the C57Bl/6J; Eln(+/-)x129X1/SvJ were more hypertensive and their arteries less compliant. In contrast, Eln(+/-) animals crossed to DBA/2J were protected from the pathologic changes associated with elastin insufficiency. Among the crosses, aortic elastin and collagen content did not correlate with quantitative vasculopathy traits. Quantitative trait locus analysis performed on F2 C57; Eln(+/-)x129 intercrosses identified highly significant peaks on chromosome 1 (LOD 9.7) for systolic blood pressure and on chromosome 9 (LOD 8.7) for aortic diameter. Additional peaks were identified that affect only Eln(+/-), including a region upstream of Eln on chromosome 5 (LOD 4.5). Bioinformatic analysis of the quantitative trait locus peaks revealed several interesting candidates, including Ren1, Ncf1, and Nos1; genes whose functions are unrelated to elastic fiber assembly, but whose effects may synergize with elastin insufficiency to predispose to hypertension and stiffer blood vessels. Real time RT-PCR studies show background-specific increased expression of Ncf1 (a subunit of the NOX2 NAPDH oxidase) that parallel the presence of increased oxidative stress in Eln(+/-) aortas. This finding raises the possibility that polymorphisms in genes affecting the generation of reactive oxygen species alter cardiovascular function in individuals with elastin haploinsufficiency through extrinsic noncomplementation.
Authors:
Beth A Kozel; Russell H Knutsen; Li Ye; Christopher H Ciliberto; Thomas J Broekelmann; Robert P Mecham
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-26     Completed Date:  2012-02-27     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  44926-36     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta / metabolism*,  pathology,  physiopathology
Blood Pressure / genetics
Crosses, Genetic
Elastin / genetics,  metabolism*
Haploinsufficiency*
Humans
Hypertension / genetics,  metabolism*,  pathology,  physiopathology
Male
Mice
Mice, Mutant Strains
NADPH Oxidase / genetics,  metabolism
Organ Size
Phenotype
Reactive Oxygen Species / metabolism
Williams Syndrome / genetics,  metabolism*,  pathology,  physiopathology
Grant Support
ID/Acronym/Agency:
HL074138/HL/NHLBI NIH HHS; HL105314/HL/NHLBI NIH HHS; HL53325/HL/NHLBI NIH HHS; K08 HL109076/HL/NHLBI NIH HHS; K08 HL109076/HL/NHLBI NIH HHS; K08 HL109076-02/HL/NHLBI NIH HHS; K12 HL089968/HL/NHLBI NIH HHS; K12 HL089968/HL/NHLBI NIH HHS; K12 HL089968-05/HL/NHLBI NIH HHS; K12-HD01487/HD/NICHD NIH HHS; R01 HL074138/HL/NHLBI NIH HHS; R01 HL074138-08/HL/NHLBI NIH HHS; R01 HL105314/HL/NHLBI NIH HHS; R01 HL105314-03/HL/NHLBI NIH HHS; R37 HL053325/HL/NHLBI NIH HHS; R37 HL053325-15/HL/NHLBI NIH HHS; T32 HD043010/HD/NICHD NIH HHS; T32 HD043010/HD/NICHD NIH HHS; T32 HD043010-10/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Reactive Oxygen Species; 9007-58-3/Elastin; EC 1.6.3.1/NADPH Oxidase; EC 1.6.3.1/neutrophil cytosolic factor 1
Comments/Corrections

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