title: Cardiac-selective expression of extracellular superoxide dismutase after systemic injection of adeno-associated virus 9 protects the heart against post-myocardial infarction left ventricular remodeling.
abstract: BACKGROUND
  Cardiac magnetic resonance imaging has not been used previously to document the attenuation of left ventricular (LV) remodeling after systemic gene delivery. We hypothesized that targeted expression of extracellular superoxide dismutase (EcSOD) via the cardiac troponin-T promoter would protect the mouse heart against both myocardial infarction (MI) and subsequent LV remodeling.
  
  
  RESULTS
  Using reporter genes, we first compared the specificity, time course, magnitude, and distribution of gene expression from adeno-associated virus (AAV) 1, 2, 6, 8, and 9 after intravenous injection. The troponin-T promoter restricted gene expression largely to the heart for all AAV serotypes tested. AAV1, 6, 8, and 9 provided early-onset gene expression that approached steady-state levels within 2 weeks. Gene expression was highest with AAV9, which required only 3.15×10(11) viral genomes per mouse to achieve an 84% transduction rate. AAV9-mediated, cardiac-selective gene expression elevated EcSOD enzyme activity in heart by 5.6-fold (P=0.015), which helped protect the heart against both acute MI and subsequent LV remodeling. In acute MI, infarct size in EcSOD-treated mice was reduced by 40% compared with controls (P=0.035). In addition, we found that cardiac-selective expression of EcSOD increased myocardial capillary fractional area and decreased neutrophil infiltration after MI. In a separate study of LV remodeling, after a 60-minute coronary occlusion, cardiac magnetic resonance imaging revealed that LV volumes at days 7 and 28 post-MI were significantly lower in the EcSOD group compared with controls.
  
  
  CONCLUSIONS
  Cardiac-selective expression of EcSOD from the cardiac troponin-T promoter after systemic administration of AAV9 provides significant protection against both acute MI and LV remodeling.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Prasad R
authors.initials: PR
authors.lastname: Konkalmatt
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Beyers
authors.forename: Daniel M
authors.initials: DM
authors.lastname: O'Connor
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Xu
authors.forename: Marc E
authors.initials: ME
authors.lastname: Seaman
authors.forename: Brent A
authors.initials: BA
authors.lastname: French
mesh_terms: D000818:Animals; D002196:Capillaries / Q000473:pathology; D000229:Dependovirus / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D020556:Neutrophil Infiltration; D011401:Promoter Regions, Genetic; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors; D020107:Troponin T / Q000235:genetics; D020257:Ventricular Remodeling
chemical_list: D020107:Troponin T; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase
keywords: AAV; LV remodeling; MI; MRI; gene therapy
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