Document Detail


A single direct injection into the left ventricular wall of an adeno-associated virus 9 (AAV9) vector expressing extracellular superoxide dismutase from the cardiac troponin-T promoter protects mice against myocardial infarction.
MedLine Citation:
PMID:  21674736     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Localized administration of a highly efficient gene delivery system in combination with a cardiac-selective promoter may provide a favorable biosafety profile in clinical applications such as coronary artery bypass graft surgery, where regions of myocardium can be readily injected to protect them against the potential threat of future ischemic events.
METHODS: Adeno-associated virus (AAV) vectors expressing luciferase or enhanced green fluorescent protein (eGFP) packaged into AAV serotypes 1, 2, 6, 8 and 9 were injected into the left ventricular (LV) wall of adult mice to determine the time course, magnitude and distribution of gene expression. An AAV9 vector expressing extracellular superoxide dismutase (EcSOD) from the cardiac troponin T (cTnT) promoter was then directly injected into the LV wall of adult mice. Myocardial infarction was induced 4 weeks after injection and infarct size was determined by triphenyltetrazolium chloride and phthalo blue staining.
RESULTS: Serotypes AAV 9, 8, 1 and 6 provided early onset of gene expression in the heart with minimal extra-cardiac gene expression. AAV9 provided the highest magnitude of gene expression. Immunostaining for eGFP showed expression spanning the anterior to posterior walls from the mid ventricle to the apex. A single direct injection of the AAV9 vector bearing EcSOD ( n  = 5) decreased the mean infarct size by 50% compared to the eGFP control group (n = 8) (44 ± 7% versus 22 ± 5%; p = 0.04).
CONCLUSIONS: AAV serotype 9 is highly efficient for cardiac gene delivery, as evidenced by early onset and high-level gene expression. AAV9-mediated, cardiac selective overexpression of EcSOD from the cTnT promoter significantly reduced infarct size in mice.
Authors:
Konkal-Matt R Prasad; Robert S Smith; Yaqin Xu; Brent A French
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The journal of gene medicine     Volume:  13     ISSN:  1521-2254     ISO Abbreviation:  J Gene Med     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-29     Completed Date:  2011-11-04     Revised Date:  2014-02-13    
Medline Journal Info:
Nlm Unique ID:  9815764     Medline TA:  J Gene Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  333-41     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiotonic Agents
Dependovirus / metabolism
Fluorescence
Gene Expression Regulation, Enzymologic / genetics,  physiology*
Gene Transfer Techniques*
Genetic Therapy / methods*
Genetic Vectors / administration & dosage
Heart Ventricles / metabolism*
Immunoblotting
Immunohistochemistry
Luciferases
Mice
Myocardial Infarction / enzymology*,  pathology,  prevention & control*
Promoter Regions, Genetic / genetics
Superoxide Dismutase / genetics,  metabolism*
Troponin T / genetics
Grant Support
ID/Acronym/Agency:
R01 HL058582/HL/NHLBI NIH HHS; R01 HL058582/HL/NHLBI NIH HHS; R01 HL092305/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Troponin T; EC 1.13.12.-/Luciferases; EC 1.15.1.1/Superoxide Dismutase

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


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