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(Circulation. 2001;103:1893.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Gene Therapy With Extracellular Superoxide Dismutase Protects Conscious Rabbits Against Myocardial Infarction

Qianhong Li, MD, PhD; Roberto Bolli, MD; Yumin Qiu, MD, PhD; Xian-Liang Tang, MD; Yiru Guo, MD; Brent A. French, PhD

From the Cardiology Research Laboratory, Division of Cardiology, University of Louisville and Jewish Hospital Heart and Lung Institute, Louisville, Ky (Q.L., R.B., Y.Q., X.-L.T., Y.G.), and the Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va.

Correspondence to Brent A. French, PhD, Department of Biomedical Engineering, University of Virginia, MR4 Bldg, Room 5021, Charlottesville, VA 22903. E-mail bf4g{at}virginia.edu

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.

Methods and 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.

Key Words: myocardial infarction • ischemia • genes • antioxidants • viruses

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