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Nuclear Factor-κB Activation Contributes to Vascular Endothelial Dysfunction via Oxidative Stress in Overweight/Obese Middle-Aged and Older Humans
Open accessAbstract
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.
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Metadata
- Authors
- Pierce, G. L., Lesniewski, L. A., Lawson, B. R., Beske, S. D., & Seals, D. R.
- Affiliations
- University of Colorado Boulder (US)
- Venue
- Circulation
- Published
- 2009-03-10
- Volume
- 119
- Issue
- 9
- Pages
- 1284-1292
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2810548
- OpenAlex
- W2160375807
- Cited by
- 262
- References
- 47
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 10 · 2023: 16 · 2022: 15 · 2021: 14 · 2020: 13 · 2019: 11 · 2018: 17 · 2017: 11 · 2016: 12 · 2015: 19 · 2014: 20 · 2013: 17 · 2012: 20
- FWCI
- 14.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG022241, AG-006537, R01AG022241, AG-000279, R37AG013038, R01AG013038, AG015897, R01AG006537, R01AG015897, AG-013038, T32AG000279)
- National Center for Research Resources (RR-00051, M01RR000051)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- NF-κB activation, endothelial dysfunction, oxidative stress, obesity, aging, salsalate, flow-mediated dilation, nitrotyrosine, vitamin C, endothelial cells, middle-aged and older adults
- MeSH terms
- NF-KappaB Inhibitor alpha, Administration, Oral, Aged, Aging, Anti-Inflammatory Agents, Non-Steroidal, Endothelium, Vascular, Female, Humans, Male, Middle Aged, Obesity, Salicylates, Tyrosine, Vasodilation, Body Mass Index, Cytokines, NF-kappa B, Oxidative Stress, Cross-Over Studies, NADPH Oxidases, I-kappa B Proteins, Overweight, Cyclooxygenase 1, Cyclooxygenase 2
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