on June 7, 2007
Published online before print June 7, 2007, doi: 10.1161/ATVBAHA.107.146852
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Submitted on April 24, 2006
Accepted on May 25, 2007
Effect of Aging, MnSOD Deficiency, and Genetic Background on Endothelial Function. Evidence for MnSOD Haploinsufficiency
Kathryn A. Brown ;
From the Departments of Pharmacology (K.A.B., F.M.F.) and Internal Medicine (S.P.D., J.J.A., F.M.F.), Cardiovascular Center, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City.
* To whom correspondence should be addressed. E-mail: frank-faraci{at}uiowa.edu.
Objective--The goal of this study was to compare vascular function, superoxide levels, and MnSOD protein expression in young (4 to 7 months) and old (22 to 24 months) MnSOD+/+ and MnSOD-deficient (MnSOD+/-) mice.
Methods and Results--Relaxation of aorta in vitro to the endothelium-dependent dilator acetylcholine (ACh) was similar in young MnSOD+/+ (n=9) and young MnSOD+/- (n=6) mice. This response was impaired in old MnSOD+/+ (n=8) mice and old MnSOD+/- mice (n=14), with dysfunction being greater in old MnSOD-deficient mice (eg, 100 µmol/L ACh produced 77±3% [mean±SE], 77±3%, 70±4%, and 57±4% relaxation in young MnSOD+/+, young MnSOD+/-, old MnSOD+/+, and old MnSOD+/- mice, respectively). The endothelial dysfunction was similar in mice on both C57BL/6 and CD-1 genetic backgrounds. In contrast to ACh, responses to the endothelium-independent dilator sodium nitroprusside were enhanced in old MnSOD+/+ and MnSOD+/- mice compared with both groups of young mice (P<0.05). Superoxide levels, as measured using lucigenin-enhanced chemiluminescence, were increased more than 2-fold in old MnSOD+/- mice compared with old MnSOD+/+ and young mice (P<0.05).
Conclusions--These data provide the first direct evidence that MnSOD halpoinsufficiency results in increased vascular oxidative stress and endothelial dysfunction with aging.
Key words: aging • oxidative stress • endothelium • mitochondria • mice
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