on October 16, 2006
Published online before print October 16, 2006, doi: 10.1161/01.HYP.0000247302.20559.3a
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Submitted on March 4, 2006
From the Departments of Internal Medicine (S.P.D., D.A.K., L.I.S., F.M.F.) and Pharmacology (F.M.F.), Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City. * To whom correspondence should be addressed. E-mail: sean-didion{at}uiowa.edu.
Abstract--The goal of this study was to test the hypothesis that loss of a single copy of the gene for CuZn superoxide dismutase (CuZnSOD) increases vascular superoxide levels and produces vascular dysfunction with aging. Responses of carotid arteries from young (7 months) and old (22 to 24 months of age) heterozygous CuZnSOD-deficient (CuZnSOD+/-) mice and their wild-type (CuZnSOD+/+) littermates were examined in vitro. Total superoxide dismutase activity in aorta was reduced by
Revised on March 20, 2006
Heterozygous CuZn Superoxide Dismutase Deficiency Produces a Vascular Phenotype With Aging
Sean P. Didion*;
30% (P<0.05) in CuZnSOD+/- mice compared with wild-type mice. Responses to acetylcholine (an endothelium-dependent agonist) produced relaxation that was similar (P>0.05) in carotid arteries from young wild-type, young CuZnSOD+/-, and old wild-type mice. In contrast, relaxation to acetylcholine was markedly impaired in old CuZnSOD+/- mice (eg, 100 µmol/L acetylcholine produced 51±5% and 96±5% relaxation in vessels from old CuZnSOD+/- and old wild-type mice, respectively). This effect was selective, because relaxation to nitroprusside (an endothelium-independent agonist) was not affected by either CuZnSOD genotype or aging. The impaired response to acetylcholine in old CuZnSOD+/- mice was restored toward normal with either tempol (a scavenger of superoxide; 1 mmol/L) or PJ34 (an inhibitor of poly-ADP-ribose polymerase; 3 µmol/L). Vascular superoxide levels were increased in aorta in old CuZnSOD+/+ mice and increased further in CuZnSOD+/- mice with aging. These findings provide the first direct evidence that normal CuZnSOD expression protects endothelial function and that deficiency in a single copy of the gene that encodes CuZnSOD produces increases in superoxide and marked impairment of endothelial function with aging.
Key words: SOD1 • superoxide • carotid artery • endothelium-dependent responses • oxidative stress • genetically altered mice
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