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

Background-We tested the hypothesis that nuclear factor-kappa B (NF-kappa 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/m(2)) middle-aged and older (age 52 to 68 years) adults. Salsalate (nonacetylated salicylate, 4500 mg/d), a compound that inhibits NF-kappa B activity, or placebo was administered for 4-day periods. Plasma salicylate concentrations reached the midtherapeutic range (21.8 +/- 1.1 mg/100 mL, P <= 0.0001 versus placebo) by day 4 of salsalate treatment. Salsalate increased expression of the inhibitor of NF-kappa B and reduced total and nuclear expression of NF-kappa 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-kappa 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. (Circulation. 2009; 119: 1284-1292.)