Document Detail


Lentiviral-human heme oxygenase targeting endothelium improved vascular function in angiotensin II animal model of hypertension.
MedLine Citation:
PMID:  20836698     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We examined the hypothesis that vascular and renal dysfunction caused by angiotensin II (Ang II) through increased levels of blood pressure, inflammatory cytokines, and oxidative stress in Sprague-Dawley rats can be prevented by lentiviral-mediated delivery of endothelial heme oxygenase (HO)-1. We targeted the vascular endothelium using a lentiviral construct expressing human HO-1 under the control of the endothelium-specific promoter VE-cadherin (VECAD-HO-1) and examined the effect of long-term human HO-1 expression on blood pressure in Ang II-mediated increases in blood pressure and oxidant stress. A bolus injection of VECAD-HO-1 into the renal artery resulted in expression of human HO-1 for up to 6-9 weeks. Sprague-Dawley rats were implanted with Ang II minipumps and treated with lentivirus carrying either the HO-1 or green fluorescent protein. Renal tissue from VECAD-HO-1-transduced rats expresses human HO-1 mRNA and proteins without an effect on endogenous HO-1. Infusion of Ang II increased blood pressure (p < 0.001) but decreased vascular relaxation in response to acetylcholine, endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) levels, and renal and plasma levels of adiponectin (p < 0.05); in contrast, plasma tumor necrosis factor-α and monocyte chemoattractant protein-1 levels increased. Ang II-treated animals had higher levels of superoxide anion and inducible nitric oxide synthase and increased urinary protein and plasma creatinine levels. Lentiviral transduction with the VECAD-HO-1 construct attenuated the increase in blood pressure (p < 0.05), improved vascular relaxation, increased plasma adiponectin, and prevented the elevation in urinary protein and plasma creatinine in Ang II-treated rats. Endothelial-specific expression of HO-1 also reduced oxidative stress and levels of inflammatory cytokines resulting in increased expression of the anti-apoptotic proteins phosphorylated AKT, phosphorylated AMP-activated protein kinase, peNOS, and eNOS. Collectively, these findings demonstrate that endothelial-specific increases in HO-1 expression attenuate Ang II hypertension and the associated vascular dysfunction that is associated with increases in adiponectin and peNOS and reductions in oxidative stress and levels of inflammatory cytokines.
Authors:
Jian Cao; Komal Sodhi; Kazuyoshi Inoue; John Quilley; Rita Rezzani; Luigi Rodella; Luca Vanella; Lucrezia Germinario; David E Stec; Nader G Abraham; Attallah Kappas
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-01-27
Journal Detail:
Title:  Human gene therapy     Volume:  22     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-15     Completed Date:  2011-06-21     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  271-82     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adiponectin / blood,  secretion
Angiotensin II / metabolism,  pharmacology*
Animals
Animals, Genetically Modified
Biological Markers / blood
Blood Pressure / drug effects
Disease Models, Animal
Endothelium, Vascular / metabolism*
Genetic Therapy*
Genetic Vectors / genetics
HEK293 Cells
Heme Oxygenase-1* / genetics,  metabolism
Humans
Hypertension / enzymology,  genetics,  therapy*
Inflammation / pathology
Kidney / drug effects,  metabolism
Lentivirus* / genetics
Nitric Oxide Synthase / metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects,  genetics
Superoxides / metabolism
Vasodilation / drug effects,  genetics
Grant Support
ID/Acronym/Agency:
DK068134/DK/NIDDK NIH HHS; HL088421/HL/NHLBI NIH HHS; HL088421-S1/HL/NHLBI NIH HHS; HL34300/HL/NHLBI NIH HHS; HL55601/HL/NHLBI NIH HHS; R01 DK056601/DK/NIDDK NIH HHS; R01 DK056601-11/DK/NIDDK NIH HHS; R01 HL088421/HL/NHLBI NIH HHS; R01 HL088421-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adiponectin; 0/Biological Markers; 11062-77-4/Superoxides; 11128-99-7/Angiotensin II; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.99.3/Heme Oxygenase-1
Comments/Corrections

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