Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin.
Lipopolysaccharide (LPS) impairs vascular function, in part by generation of reactive oxygen species. One goal of this study was to determine whether gene transfer of extracellular SOD (ECSOD) improves vascular responsiveness in LPS-treated rats. A second goal was to determine whether effects of ECSOD are dependent on the heparin-binding domain of the enzyme, which facilitates binding of ECSOD to the outside of cells. Adenoviruses containing ECSOD (AdECSOD), ECSOD with deletion of its heparin-binding domain (AdECSOD-HBD), or a control virus (AdLacZ) were injected intravenously into rats. Three days later, vehicle or LPS (10 mg/kg ip) was injected. After 24 h, vascular reactivity was examined in aortic rings in vitro. Maximum relaxation to acetylcholine was 95 +/- 1% (means +/- SE) after AdlacZ plus vehicle and 77 +/- 3% after AdlacZ plus LPS (P < 0.05). Responses to calcium ionophore A-23187 and submaximal concentrations of nitroprusside also were impaired by LPS. Gene transfer of ECSOD, but not AdECSOD-HBD, improved (P < 0.05) relaxation to acetylcholine and A-23187 after LPS. Maximum relaxation to acetylcholine was 88 +/- 3% after LPS plus AdECSOD. Superoxide was increased in aorta after LPS, and the levels were reduced after AdECSOD but not AdECSOD-HBD. LPS-induced adhesion of leukocytes to aortic endothelium was reduced by AdECSOD but not by AdECSOD-HBD. We conclude that after gene transfer in vivo, binding of ECSOD to arteries effectively decreases the numbers of adherent leukocytes and levels of superoxide and improves impaired endothelium-dependent relaxation produced by LPS.
Lund
Donald D
DD
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Gunnett
Carol A
CA
Chu
Yi
Y
Brooks
Robert M
RM
Faraci
Frank M
FM
Heistad
Donald D
DD
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D045604:Extracellular Fluid / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects
D008070:Lipopolysaccharides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013482:Superoxide Dismutase