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(Circulation Research. 2007;100:1659.)
© 2007 American Heart Association, Inc.

Clinical Research

Direct Evidence of Endothelial Oxidative Stress With Aging in Humans

Relation to Impaired Endothelium-Dependent Dilation and Upregulation of Nuclear Factor-B

Anthony J. Donato, Iratxe Eskurza, Annemarie E. Silver, Adam S. Levy, Gary L. Pierce, Phillip E. Gates, Douglas R. Seals

From the Department of Integrative Physiology, University of Colorado, Boulder.

Correspondence to Anthony J. Donato, PhD, Department of Integrative Physiology, University of Colorado at Boulder, 354 UCB, Boulder, CO 80309. E-mail tony.donato{at}colorado.edu

Aging is associated with impaired vascular endothelial function, as indicated in part by reduced endothelium-dependent dilation (EDD). Decreased EDD with aging is thought to be related to vascular endothelial cell oxidative stress, but direct evidence is lacking. We studied 95 healthy men: 51 young (23±1 years) and 44 older (63±1 years). EDD (brachial artery flow-mediated dilation) was 50% lower in older versus young men (3.9±0.3% versus 7.6±0.3%, P<0.01; n=42 older/n=51 young). Abundance of nitrotyrosine (quantitative immunofluorescence), an oxidatively modified amino acid and marker of oxidative stress, was higher in endothelial cells (ECs) obtained from the brachial artery (1.25±0.12 versus 0.61±0.11 nitrotyrosine intensity/human umbilical vein EC [HUVEC] intensity, P=0.01; n=11 older/n=11 young) and antecubital veins (0.55±0.04 versus 0.34±0.03, P<0.05; n=19 older/n=17 young) of older men. Flow-mediated dilation was inversely related to arterial EC nitrotyrosine expression (r=–0.62, P=0.01; n=22). In venous samples, EC expression of the oxidant enzyme NAD(P)H oxidase-p47^phox was higher in older men (0.71±0.05 versus 0.57±0.05 NAD[P]H oxidase-p47^phox intensity/HUVEC intensity, P<0.05; n=19 older/n=18 young), whereas xanthine oxidase and the antioxidant enzymes cytosolic and mitochondrial superoxide dismutase and catalase were not different between groups. Nuclear factor-B p65, a component of the redox-sensitive nuclear transcription factor nuclear factor-B, was elevated in both arterial (0.73±0.07 versus 0.53±0.05 NF-B p65 intensity/HUVEC intensity, P<0.05; n=9 older/n=12 young) and venous (0.65±0.07 versus 0.34±0.05, P<0.01; n=13 older/n=15 young) EC samples of older men and correlated with nitrotyrosine expression (r=0.51, P<0.05 n=16). These results provide direct support for the hypothesis that endothelial oxidative stress develops with aging in healthy men and is related to reductions in EDD. Increased expression of NAD(P)H oxidase and nuclear factor-B may contribute to endothelial oxidative stress with aging in humans.

Key Words: flow-mediated dilation • NAD(P)H oxidase • xanthine oxidase • antioxidants

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