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

• Published in: Circulation (New York, N.Y.) Vol. 119; no. 9; pp. 1284 - 1292
• Main Authors: Pierce, Gary L., Lesniewski, Lisa A., Lawson, Brooke R., Beske, Stacy D., Seals, Douglas R.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 10.03.2009
• Subjects: Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Medical sciences; Vertebrates: cardiovascular system; Human; Obesity; Oxidative stress; Senescence; Nutrition disorder; Brachial artery; Cardiovascular disease; Inflammation; Endothelium; Overweight; Endothelial dysfunction; aging; Nutritional status
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.108.804294

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.