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(Circulation. 2009;119:1284-1292.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Nuclear Factor-B Activation Contributes to Vascular Endothelial Dysfunction via Oxidative Stress in Overweight/Obese Middle-Aged and Older Humans

Gary L. Pierce, PhD; Lisa A. Lesniewski, PhD; Brooke R. Lawson, MS; Stacy D. Beske, PhD; Douglas R. Seals, PhD

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

Correspondence to Gary L. Pierce, PhD, Department of Integrative Physiology, UCB 354, University of Colorado at Boulder, Boulder, CO 80309. E-mail gpierce{at}colorado.edu

Received July 2, 2008; accepted November 4, 2008.

Background— We tested the hypothesis that nuclear factor-B (NF-B) activity contributes to vascular endothelial dysfunction with aging and obesity in humans.

Methods and Results— We conducted a randomized, double-blind, placebo-controlled crossover study in 14 nondiabetic overweight or obese (body mass index 25 kg/m²) middle-aged and older (age 52 to 68 years) adults. Salsalate (nonacetylated salicylate, 4500 mg/d), a compound that inhibits NF-B activity, or placebo was administered for 4-day periods. Plasma salicylate concentrations reached the midtherapeutic range (21.8±1.1 mg/100 mL, P0.0001 versus placebo) by day 4 of salsalate treatment. Salsalate increased expression of the inhibitor of NF-B and reduced total and nuclear expression of NF-B in endothelial cells obtained from the subjects (all P<0.05). Salsalate increased brachial artery flow-mediated dilation by 74% (from 4.0±0.4% to 6.6±0.5%, P<0.001) but did not affect endothelium-independent dilation (P=0.83). The change in brachial artery flow-mediated dilation with salsalate was inversely related to baseline flow-mediated dilation (r=–0.77, P<0.01). Infusion of vitamin C increased brachial artery flow-mediated dilation during placebo (P<0.001) but not after salsalate (P=0.23). Salsalate reduced nitrotyrosine (P=0.06) and expression of NADPH oxidase p47^phox (P<0.05) in endothelial cells obtained from the subjects but did not influence circulating or endothelial cell inflammatory proteins.

Conclusions— Our findings provide the first direct evidence that NF-B, in part via stimulation of oxidative stress, plays an important role in mediating vascular endothelial dysfunction in overweight and obese middle-aged and older humans.

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