Document Detail


Chronic recurrent myocardial ischemic injury is significantly attenuated by pre-emptive adeno-associated virus heme oxygenase-1 gene delivery.
MedLine Citation:
PMID:  16458149     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: We assessed the hypothesis that overexpression of the antioxidant enzyme heme oxygenase (HO)-1 may protect against chronic recurrent ischemia/reperfusion injury. BACKGROUND: Multiple and recurring episodes of myocardial ischemia can result in significant myocardial damage, including myocyte death, fibrosis, and wall thinning, leading to impaired ventricular function and cardiac failure. METHODS: In this study we used a closed-chest rodent model of chronic recurring myocardial ischemia and reperfusion to investigate the efficacy of pre-emptive gene therapy in overexpressing the antioxidant enzyme HO-1, using adeno-associated virus (AAV)-2 as the delivery vector. RESULTS: We show that constitutive overexpression of HO-1 can prevent myocardial wall thinning, inflammation, fibrosis, and deterioration of cardiac function (as measured by echocardiography, histology, and immunohistochemistry) induced by repeated transient myocardial ischemia and reperfusion injury. With HO-1 therapy, there was a significant reduction in apoptosis as determined by levels of markers of survival proteins and terminal deoxynucleotidyltransferase dUTP nick end-labeling staining. This prevention of tissue damage was also associated with reduction in superoxide generation. CONCLUSIONS: Taken together we provide the first evidence of the therapeutic efficacy of pre-emptive AAV-HO-1 delivery for prevention against multiple ischemic injury. This approach protects myocytes by simultaneously activating protective response and inhibiting pathological left ventricular remodeling and, therefore, may be a useful cardio-protective strategy for patients with coronary artery disease at a high risk for recurrent myocardial ischemia.
Authors:
Alok S Pachori; Luis G Melo; Lunan Zhang; Scott D Solomon; Victor J Dzau
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-01-18
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  47     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-06     Completed Date:  2006-03-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  635-43     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Dependovirus / genetics
Gene Therapy*
Genetic Vectors
Heme Oxygenase-1 / genetics*,  metabolism,  therapeutic use
In Situ Nick-End Labeling
Male
Myocardial Reperfusion Injury / genetics,  metabolism,  pathology,  prevention & control*
Myocardium / metabolism,  pathology
Rats
Rats, Sprague-Dawley
Recurrence
Superoxides / metabolism
Grant Support
ID/Acronym/Agency:
HL 35610/HL/NHLBI NIH HHS; HL 69601-01/HL/NHLBI NIH HHS; HL 72010/HL/NHLBI NIH HHS; HL 73219/HL/NHLBI NIH HHS; HL58516/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
11062-77-4/Superoxides; 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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