title: Extracellular but not cytosolic superoxide dismutase protects against oxidant-mediated endothelial dysfunction.
abstract: Superoxide (O2 (•-)) contributes to the development of cardiovascular disease. Generation of O2 (•-) occurs in both the intracellular and extracellular compartments. We hypothesized that the gene transfer of cytosolic superoxide dismutase (SOD1) or extracellular SOD (SOD3) to blood vessels would differentially protect against O2 (•-)-mediated endothelial-dependent dysfunction. Aortic ring segments from New Zealand rabbits were incubated with adenovirus (Ad) containing the gene for Escherichia coli β-galactosidase, SOD1, or SOD3. Activity assays confirmed functional overexpression of both SOD3 and SOD1 isoforms in aorta 24 h following gene transfer. Histochemical staining for β-galactosidase showed gene transfer occurred in the endothelium and adventitia. Next, vessels were prepared for measurement of isometric tension in Kreb's buffer containing xanthine. After precontraction with phenylephrine, xanthine oxidase impaired relaxation to the endothelium-dependent dilator acetylcholine (ACh, max relaxation 33±4% with XO vs. 64±3% without XO, p<0.05), whereas relaxation to the endothelium-independent dilator sodium nitroprusside was unaffected. In the presence of XO, maximal relaxation to ACh was improved in vessels incubated with AdSOD3 (55±2%, p<0.05 vs. control) but not AdSOD1 (34±4%). We conclude that adenoviral-mediated gene transfer of SOD3, but not SOD1, protects the aorta from xanthine/XO-mediated endothelial dysfunction. These data provide important insight into the location and enzymatic source of O2 (•-) production in vascular disease.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Foresman
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Miller
mesh_terms: D063194:Adventitia / Q000378:metabolism / Q000821:virology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D000229:Dependovirus / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D011817:Rabbits; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D019820:Xanthine / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: D016877:Oxidants; D020011:Protective Agents; D013481:Superoxides; D019820:Xanthine; D010656:Phenylephrine; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase
keywords: Endothelial dysfunction; Gene transfer; Oxygen free radicals; Superoxide dismutase
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