| Lentiviral-human heme oxygenase targeting endothelium improved vascular function in angiotensin II animal model of hypertension. | |
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MedLine Citation:
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PMID: 20836698 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-01-27 |
Journal Detail:
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Title: Human gene therapy Volume: 22 ISSN: 1557-7422 ISO Abbreviation: Hum. Gene Ther. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-15 Completed Date: 2011-06-21 Revised Date: 2012-03-27 |
Medline Journal Info:
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Nlm Unique ID: 9008950 Medline TA: Hum Gene Ther Country: United States |
Other Details:
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Languages: eng Pagination: 271-82 Citation Subset: IM |
Affiliation:
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Department of Physiology and Pharmacology, The University of Toledo, Toledo, OH 43614, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adiponectin
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blood,
secretion Angiotensin II / metabolism, pharmacology* Animals Animals, Genetically Modified Biological Markers / blood Blood Pressure / drug effects Disease Models, Animal Endothelium, Vascular / metabolism* Gene 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:
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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 DK056601-11/DK/NIDDK NIH HHS; R01 DK056601-12/DK/NIDDK NIH HHS; R01 HL088421-04/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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