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

• DOI: 10.1161/circulationaha.108.804294
• Publication Date: 2009-02-24T02:11:02Z
• Authors: Gary L. Pierce; Lisa A. Lesniewski; Brooke R. Lawson; Stacy D. Beske; Douglas R. Seals
• Keywords: Male; 0301 basic medicine; 2. Zero hunger; Aging; Cross-Over Studies; Anti-Inflammatory Agents, Non-Steroidal; NF-kappa B; Administration, Oral; NADPH Oxidases; Middle Aged; Overweight; Body Mass Index; 3. Good health; 03 medical and health sciences; NF-KappaB Inhibitor alpha; Cyclooxygenase 2; Cyclooxygenase 1; Cytokines; Humans; Female; I-kappa B Proteins; Endothelium, Vascular; Obesity; Aged

Background—

We tested the hypothesis that nuclear factor-κB (NF-κB) 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-κB 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-κB and reduced total and nuclear expression of NF-κB 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-κB, 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.