Gene therapy with extracellular superoxide dismutase protects conscious rabbits against myocardial infarction.
BACKGROUND
Extracellular superoxide dismutase (Ec-SOD) may protect the heart against myocardial infarction (MI) because of its extended half-life and capacity to bind heparan sulfate proteoglycans on cellular surfaces. Accordingly, we used direct gene transfer to increase systemic levels of Ec-SOD and determined whether this gene therapy could protect against MI.


RESULTS
The cDNA for human Ec-SOD was incorporated into a replication-deficient adenovirus (Ad5/CMV/Ec-SOD). Injection of this virus produced a high level of Ec-SOD in the liver, which was redistributed to the heart and other organs by injection of heparin. Untreated rabbits (group I) underwent a 30-minute coronary occlusion and 3 days of reperfusion. For comparison, preconditioned rabbits (group II) underwent a sequence of six 4-minute-occlusion/4-minute-reperfusion cycles 24 hours before the 30-minute occlusion. Control-treated rabbits (group III) were injected intravenously with Ad5/CMV/nls-LacZ, and gene-therapy rabbits (group IV) were injected with Ad5/CMV/Ec-SOD 3 days before the 30-minute occlusion. Both groups treated with Ad5 received intravenous heparin 2 hours before the 30-minute occlusion. Infarct size (percent risk area) was similar in groups I (57+/-6%) and III (58+/-5%). Ec-SOD gene therapy markedly reduced infarct size to 25+/-4% (P<0.01, group IV versus group III), a protection comparable to that of the late phase of ischemic preconditioning (29+/-3%, P<0.01 group II versus group I).


CONCLUSIONS
Direct gene transfer of the cDNA encoding membrane-bound Ec-SOD affords powerful cardioprotection, providing proof of principle for the effectiveness of antioxidant gene therapy against MI.
Li
Q
Q
Cardiology Research Laboratory, Division of Cardiology, University of Louisville and Jewish Hospital Heart and Lung Institute, Louisville, KY, USA.
Bolli
R
R
Qiu
Y
Y
Tang
X L
XL
Guo
Y
Y
French
B A
BA
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D001794:Blood Pressure / Q000502:physiology; D019556:COS Cells; D003243:Consciousness; D016166:Free Radical Scavengers / Q000378:metabolism / Q000627:therapeutic use; D015870:Gene Expression; D015316:Genetic Therapy; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000150:complications; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use
D016166:Free Radical Scavengers; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D013482:Superoxide Dismutase