Abstract 5459: Vascular Endothelial Nuclear Factor-κB Contributes to Endothelial Dysfunction Via Oxidative Stress in Middle-Aged and Older Overweight/Obese Humans
We recently reported that vascular endothelial NFκB, a key proinflammatory nuclear transcription factor associated with the development of atherosclerosis, modulates endothelial dysfunction (impaired endothelium-dependent dilation, EDD) in overweight/obese middle-aged and older (MA/O) men. MA/O normal- and overweight/obese adults also demonstrate oxidative stress-mediated suppression of EDD and increased endothelial nitrotyrosine, a marker of vascular oxidative stress. Therefore, we tested the hypothesis that NFκB-associated vascular inflammation mediates endothelial dysfunction via vascular oxidative stress in MA/O overweight/obese humans. Salsalate, a non-acetylated aspirin that inhibits NFκB at high doses, was ingested (4500 mg/d; therapeutic [plasma] 21.8 ± 1.2 mg/dl, mean ± SE) for 4 days (randomized, placebo-controlled, double-blind crossover design) by 14 non-diabetic overweight or obese MA/O men and women (11 M/3 F; 61 ± 1 yrs; BMI, 31 ± 2 kg/m2). Salsalate reduced total (−27%: 0.39 ± 0.03 vs. 0.54 ± 0.08 intensity/HUVEC intensity, P<0.05) and nuclear (−20%: 0.46 ± 0.05 vs. 0.58 ± 0.08 intensity/HUVEC intensity, P<0.05) expression of NFκB p65 (quantitative immunofluorescence), and increased the inhibitor of NFκB (IκBα) in venous endothelial cells obtained from the subjects. Salsalate increased EDD (brachial artery flow-mediated dilation) by 65% (6.6 ± 0.5 vs. 4.0 ± 0.7 Δ%, P<0.001) without affecting brachial artery endothelium-independent dilation to sublingual nitroglycerin (20.9 ± 2.0 vs. 20.7 ± 1.7 Δ%, P>0.05). In a subset of 8 subjects, acute intravenous infusion of supraphysiological concentrations of vitamin C, a potent antioxidant, improved EDD under placebo conditions (+37%; 6.2 ± 1.2 vs. 4.5 ± 1.1 Δ%, P<0.001), but had no effect after Salsalate (7.5 ± 0.8 vs. 7.2 ± 0.6 Δ%, P>0.05). Salsalate reduced nitrotyrosine (−28%, P=0.06) and NADPH oxidase p47phox (−27%, P<0.05), a key subunit required for NADPH oxidase production of cellular oxidants, in endothelial cells obtained from the subjects. These results support the idea that NFκB-mediated suppression of vascular endothelial function in MA/O overweight/obese humans is mediated at least in part by oxidative stress.