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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1941.)
© 2007 American Heart Association, Inc.

Vascular Biology

Effect of Aging, MnSOD Deficiency, and Genetic Background on Endothelial Function

Evidence for MnSOD Haploinsufficiency

Kathryn A. Brown; Sean P. Didion; Jon J. Andresen; Frank M. Faraci

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.

Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, E315-GH, Carver College of Medicine, University of Iowa, Iowa City, IA 52242. 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.

This study examined the impact of genetic deficiency in MnSOD on oxidative stress and vascular function in aged mice. Using mice on 2 different genetic backgrounds, the data obtained provide the first direct evidence that MnSOD halpoinsufficiency increases vascular oxidative stress and endothelial dysfunction with aging.

Key Words: aging • oxidative stress • endothelium • mitochondria • mice

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