Document Detail


Overexpression of endothelial nitric oxide synthase improves endothelium-dependent vasodilation in arteries infused with helper-dependent adenovirus.
MedLine Citation:
PMID:  22906141     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adenoviral vectors (Ad) are useful tools for in vivo gene transfer into endothelial cells. However, endothelium-dependent vasodilation is impaired after Ad infusion, and this impairment is not prevented by use of advanced-generation "helper-dependent" (HD) Ad that lack all viral genes. We hypothesized that endothelium-dependent vasodilation could be improved in Ad-infused arteries by overexpression of endothelial nitric oxide synthase (eNOS). We tested this hypothesis in hyperlipidemic, atherosclerosis-prone rabbits because HDAd will likely be used for treating and preventing atherosclerosis. Moreover, the consequences of eNOS overexpression might differ in normal and atherosclerosis-prone arteries and could include atherogenic effects, as reported in transgenic mice. We cloned rabbit eNOS and constructed an HDAd that expresses it. HDAdeNOS increased NO production by cultured endothelial cells and increased arterial eNOS mRNA in vivo by ∼10-fold. Compared to arteries infused with a control HDAd, HDAdeNOS-infused arteries of hyperlipidemic rabbits had significantly improved endothelium-dependent vasodilation, and similar responses to phenylephrine and nitroprusside. Moreover, infusion of HDAdeNOS had local atheroprotective effects including large, significant decreases in intimal lipid accumulation and arterial tumor necrosis factor (TNF)-α expression (p≤0.04 for both). HDAdeNOS infusion yields a durable (≥2 weeks) increase in arterial eNOS expression, improves vasomotor function, and reduces artery wall inflammation and lipid accumulation. Addition of an eNOS expression cassette improves the performance of HDAd, has no harmful effects, and may reduce atherosclerotic lesion growth.
Authors:
Bo Jiang; Liang Du; Rowan Flynn; Nagadhara Dronadula; Jingwan Zhang; Francis Kim; David Dichek
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-24
Journal Detail:
Title:  Human gene therapy     Volume:  23     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-13     Completed Date:  2013-04-19     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1166-75     Citation Subset:  IM    
Affiliation:
Division of Cardiology, Department of Medicine, University of Washington, Seattle, 98195, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics*
Animals
Arteries / metabolism*
Atherosclerosis / genetics,  metabolism
Carotid Arteries / metabolism,  pathology
Cattle
Cell Adhesion Molecules / genetics,  metabolism
Cytokines / genetics,  metabolism
Endothelial Cells / metabolism
Endothelium, Vascular / metabolism*
Enzyme Activation
Gene Expression
Genetic Vectors / administration & dosage,  genetics*
Male
Nitric Oxide Synthase Type III / genetics*,  metabolism
RNA, Messenger / genetics,  metabolism
Rabbits
Vasodilation / genetics*
Grant Support
ID/Acronym/Agency:
HL076226/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cell Adhesion Molecules; 0/Cytokines; 0/RNA, Messenger; EC 1.14.13.39/Nitric Oxide Synthase Type III
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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