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

Abstract

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 Ն25 kg/m 2 ) 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 (21.8Ϯ1.1 mg/100 mL, PՅ0.0001 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 PϽ0.05). Salsalate increased brachial artery flow-mediated dilation by 74% (from 4.0Ϯ0.4% to 6.6Ϯ0.5%, PϽ0.001) but did not affect endotheliumindependent dilation (Pϭ0.83). The change in brachial artery flow-mediated dilation with salsalate was inversely related to baseline flow-mediated dilation (rϭϪ0.77, PϽ0.01). Infusion of vitamin C increased brachial artery flow-mediated dilation during placebo (PϽ0.001) but not after salsalate (Pϭ0.23). Salsalate reduced nitrotyrosine (Pϭ0.06) and expression of NADPH oxidase p47 phox (PϽ0.05) 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. Key Words: endothelium Ⅲ brachial artery Ⅲ obesity Ⅲ inflammation Ⅲ aging V ascular endothelial dysfunction plays an important role in the increased risk of cardiovascular diseases with aging, 1 particularly in overweight and obese adults. 2,3 Inflammation and oxidative stress are thought to be important processes by which aging and increased adiposity lead to development of vascular endothelial dysfunction 4 -7 ; however, the molecular mechanisms involved, particularly in humans, are poorly understood. Clinical Perspective p 1292The nuclear transcription factor nuclear factor-B (NF-B) and its inhibitory protein, inhibitor of NF-B (IB), compose a tightly controlled system that regulates the inflammatory and redox states of vascular endothelial cells. 8,9 Data from animal and cell culture models implicate NF-B in both age-and obesity-associated vascular endothelial dysfunction. 10,11 Recently, we found that endothelial cells obtained from overweight/obese 12 and older 13,14 nondiabetic adults have greater protein expression of NF-B than normal-weight and young adults, respectively. Moreover, NF-B was positively related to nitrotyrosine, a cellular marker of oxidative stress. 13 Endothelial cell expression of the oxidant-producing enzyme NADPH oxidase also was greater in overweight/obese 12 and older 13 adults. Taken together, these ...

Association Between Endothelial Function (Assessed on Reactive Hyperemia Peripheral Arterial Tonometry) and Obstructive Sleep Apnea, Visceral Fat Accumulation, and Serum Adiponectin

“…4 The relationship between obesity and endothelial inflammation or increased vascular oxidative stress has also been reported. 28, 29 These reports,…”

“…19 Nuclear factor-κB (NF-κB) activation, in part via stimulation of oxidative stress, plays an important role in mediating vascular endothelial dysfunction in overweight and obese humans. 29 Therefore, given that it is a well known phenomenon that intermittent hypoxia mimicking OSA activates NF-κB, 30 it might be reasonable that endothelial function as measured by RHI would worsen when patients had severe OSA and visceral obesity concomitantly. The present results support the idea that OSA exacerbates the cardiometabolic risk attributed to obesity or visceral obesity.…”

AMPK activation—protean potential for boosting healthspan

“…This may explain why the diabetic glycemic control achieved with salsalate therapy tends to be less impressive than that seen with metformin or berberine-and much of the glycemic reduction it does achieve may be mediated by downregulation of IkappaB kinase activation (Goldfine et al 2010;Faghihimani et al 2013;Yin et al 1998). Nonetheless, employing salsalate in conjunction with either metformin or berberine may be an attractive option for managing diabetes, vascular disorders, or cancer; (McCarty 2010;Pierce et al 2009;Lesniewski et al 2011;McCarty and Block 2006) these agents may complement each other with respect to AMPK activation, NF-kappaB inhibition, and control of oxidative stress.…”

Use of the most recent reagent (CuF) for stimulation of NO synthesis by the medicinal leech salivary cell secretion in the cultures of human endothelium cells (HUVEC) and in rat cardiomiocytes

“…Кроме того, обратимое нитрозилирование белков -это один из известных путей регуляции клеточных процессов. Показано [40], что NO регулирует иммунную систему путем S-нитрозилирования известного фактора транскрипции NF-каппа B. Разбалансировка регуляции активности этого фактора в эндотелии при старении -одна из причин заболеваний сердечно-сосудистой системы у пожилых людей [41]. В эндотелиальной клетке NO контролирует также сигнальные пути, связанные с активацией рецепторов "врожденного иммунитета" TLR, через S-нитрозилирование универсального белка-адаптора MyD88 и этот процесс напрямую зависит от активности eNOS [42].…”

“…В эндотелиальной клетке NO контролирует также сигнальные пути, связанные с активацией рецепторов "врожденного иммунитета" TLR, через S-нитрозилирование универсального белка-адаптора MyD88 и этот процесс напрямую зависит от активности eNOS [42]. Нитрозилирование перечисленных белков снижает воспалительные реакции в острой фазе иммунного ответа и благоприятно для пожилого организма, так как снижает активность фактора NF-каппа B [41]. Для получения представлений о влиянии ССК на уровень eNOS в клетках HUVEC, мы определяли в них количество мРНК eNOS и iNOS.…”