| A hypoxic inducible factor-1 alpha hybrid enhances collateral development and reduces vascular leakage in diabetic rats. | |
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MedLine Citation:
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PMID: 19291676 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Diabetes mellitus is a common comorbidity of atherosclerosis. Hypoxia-inducible factor-1 (HIF-1) is the master regulator of the angiogenic response to hypoxia. METHODS: We studied the effects of adenoviral vectors expressing a constitutively active HIF-1 alpha hybrid (Ad2/HIF-1 alpha/VP16) or vascular endothelial growth factor (Ad2/VEGF) on collateral development and vascular leakiness in a diabetic rat model of hindlimb ischemia. RESULTS: After the removal of the right femoral artery, the mRNA levels of VEGF, angiopoietin-1 and angiopietin-4 in the calf muscles, as measured by Taqman reverse transcriptase-polymerase chain reaction, were transiently elevated in Zucker lean (ZL) but not Zucker diabetic fatty (ZDF) rats. The angiographic score, as determined by post-mortem angiography, was significantly lower in ZDF animals 35 days after surgery compared to their ZL counterparts. In separate animals, intramuscular injection of Ad2/HIF-1a/VP16 and Ad/2VEGF into the thigh muscles significantly increased the angiographic score and capillary density 21 and 35 days after the injection compared to Ad2/CMVEV (a vector expressing no transgene) or vehicle. After the injection of Ad2/CMVEV or vehicle, the Evans-blue dye content in the thigh muscles was significantly higher in ZDF rats than their ZL counterparts. Ad2/HIF-1 alpha/VP16 but not Ad2/VEGF reduced tissue Evans blue dye content. CONCLUSIONS: The endogenous angiogenic response to ischemia was impaired in ZDF rats, possibly due to down-regulation of angiogenic factors. Ad2/HIF-1 alpha/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF-1 alpha angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity. |
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Authors:
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Hidetoshi Kajiwara; Zhengyu Luo; Adam J Belanger; Akihiro Urabe; Karen A Vincent; Geoffrey Y Akita; Seng H Cheng; Seibu Mochizuki; Richard J Gregory; Canwen Jiang |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The journal of gene medicine Volume: 11 ISSN: 1521-2254 ISO Abbreviation: J Gene Med Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-04-27 Completed Date: 2009-07-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9815764 Medline TA: J Gene Med Country: England |
Other Details:
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Languages: eng Pagination: 390-400 Citation Subset: IM |
Copyright Information:
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(c) 2009 John Wiley & Sons, Ltd. |
Affiliation:
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Genzyme Corporation, Framingham, MA 01701-9322, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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genetics Animals Blood Vessels / pathology* Body Weight Collateral Circulation / physiology* DNA / genetics Diabetes Mellitus, Experimental / physiopathology* Femoral Artery / surgery Gene Expression Regulation Gene Transfer Techniques Genetic Vectors / genetics Hemoglobin A, Glycosylated / metabolism Hindlimb / blood supply Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Immunohistochemistry Injections, Intramuscular Ischemia Neovascularization, Physiologic / genetics Rats Rats, Zucker Recombinant Proteins / metabolism* Transgenes |
| Chemical | |
Reg. No./Substance:
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0/Hemoglobin A, Glycosylated; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Recombinant Proteins; 9007-49-2/DNA |
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