From the Molecular Cardiology Unit and the Experimental Research
Laboratory of the Division of Cardiology (Q.L., R.B., Y.Q., X-L.T., B.A.F.),
the Department of Anatomic Pathology (S.S.M.), and the Center for Genetics and
Molecular Medicine (B.A.F.), University of Louisville, Louisville, Ky.
Correspondence to Brent A. French, PhD, Department of Biomedical Engineering, University of Virginia Health Sciences Center, Stacey Hall, 1105 W Main St, Charlottesville, VA 22903.
Background—Administration of Cu/Zn
superoxide dismutase (SOD) without catalase fails to alleviate
myocardial stunning, but extracellular SOD (Ec-SOD) may be more
effective because it binds to heparan sulfate proteoglycans on the
cellular glycocalyx. We therefore used in vivo gene transfer to
increase systemic levels of Ec-SOD and determined whether this gene
therapy protects against myocardial stunning.
Methods and Results—The cDNA for human Ec-SOD was cloned behind
the cytomegalovirus (CMV) promoter and incorporated into a
replication-deficient adenovirus (Ad5/CMV/Ec-SOD). Injection of this
virus (2x108 pfu/kg IV) produced high levels of Ec-SOD in
the liver, which could be redistributed to the heart and other organs
by injection of heparin. Conscious rabbits underwent a sequence of six
4-minute coronary occlusion/4-minute reperfusion cycles for 3
consecutive days starting 3 days after intravenous
injection of Ad5/CMV/Ec-SOD or Ad5/CMV/nls/LacZ (negative control).
Both groups were given heparin (2000 U/kg IV) 2 hours before the first
sequence of occlusions. The severity of myocardial stunning was
measured as the total deficit of LV wall thickening after the last
reperfusion. On day 1, the total deficit of wall thickening was
markedly decreased in Ad5/CMV/Ec-SOD rabbits versus controls and
similar to that seen on days 2 and 3 in controls.
Conclusions—The results demonstrate that in vivo gene transfer of
the cDNA encoding Ec-SOD provides the heart with substantial protection
against myocardial stunning without the need for concomitant
administration of catalase. The present observations provide the
basis for controlling gene therapy at the posttranslational level and
for simultaneously protecting multiple organs from oxidant
stress.
© 1998 American Heart Association, Inc.
Basic Science Reports
Gene Therapy With Extracellular Superoxide Dismutase Attenuates Myocardial Stunning in Conscious Rabbits
Key Words: genes • superoxide dismutase • free radicals • stunning, myocardial • ischemia • reperfusion
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