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(Stroke. 2003;34:434.)
© 2003 American Heart Association, Inc.

Original Contributions

Gene Transfer of Extracellular Superoxide Dismutase Reduces Cerebral Vasospasm After Subarachnoid Hemorrhage

Yoshimasa Watanabe, MD; Yi Chu, PhD; Jon J. Andresen, BA; Hiroshi Nakane, MD; Frank M. Faraci, PhD Donald D. Heistad, MD

From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa.

Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242. E-mail donald-heistad{at}uiowa.edu

Background and Purpose— Superoxide may play an important role in cerebral vasospasm after subarachnoid hemorrhage (SAH). Our first goal was to determine the effect of gene transfer of extracellular superoxide dismutase (ECSOD) on vasospasm after experimental SAH. Our second goal was to determine whether tissue binding of ECSOD via the heparin-binding domain (HBD) is important for the effect of the enzyme. Thus, we examined effects of gene transfer of ECSOD with the HBD deleted (ECSODHBD).

Methods— Adenovirus expressing human ECSOD (AdECSOD), ECSODHBD (AdECSODHBD), or no transgene (AdBglII) was injected into the cisterna magna of anesthetized rabbits 30 minutes after induction of experimental SAH. Cerebral angiography, an assay for ECSOD activity in cerebrospinal fluid (CSF), and Western blotting for human ECSOD in the basilar artery were performed.

Results— Baseline diameter of the basilar artery averaged 0.77±0.01 mm (mean±SEM) and was similar in all treatment groups. Decreases in diameter of the basilar artery 2 days after SAH were smaller after AdECSOD (11±3%; n=10) than after AdBglII (25±4%; n=7; P<0.05). ECSOD activity was not detected in CSF before SAH and gene transfer. Of 8 rabbits treated with AdECSOD, in which ECSOD activity in CSF was measured after SAH, 5 animals had detectable ECSOD activity in CSF (46±13 U/mL). In these 5 rabbits, the diameter decreased by only 6±3%, and ECSOD protein was detected in the basilar artery. After AdECSODHBD (n=4), despite high levels of ECSOD activity in CSF (91±19 U/mL), vessel diameter decreased by 20±2%, and no ECSODHBD protein was detected in the basilar artery.

Conclusions— Gene transfer of ECSOD reduces cerebral vasospasm after experimental SAH. Tissue binding of the enzyme is essential for cerebral vascular effects of ECSOD.

Key Words: gene transfer • subarachnoid hemorrhage • superoxide dismutase • vasospasm, intracranial • rabbits

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