Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans

Circulation. 2009 Mar 10;119(9):1284-92. doi: 10.1161/CIRCULATIONAHA.108.804294. Epub 2009 Feb 23.

Abstract

Background: We tested the hypothesis that nuclear factor-kappaB (NF-kappaB) 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 > or =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-kappaB activity, or placebo was administered for 4-day periods. Plasma salicylate concentrations reached the midtherapeutic range (21.8+/-1.1 mg/100 mL, P< or =0.0001 versus placebo) by day 4 of salsalate treatment. Salsalate increased expression of the inhibitor of NF-kappaB and reduced total and nuclear expression of NF-kappaB 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-kappaB, 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Aged
  • Aging / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage*
  • Anti-Inflammatory Agents, Non-Steroidal / blood
  • Body Mass Index
  • Cross-Over Studies
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Female
  • Humans
  • I-kappa B Proteins / metabolism
  • Male
  • Middle Aged
  • NADPH Oxidases / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Obesity / metabolism*
  • Obesity / pathology
  • Overweight / metabolism*
  • Overweight / pathology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Salicylates / administration & dosage*
  • Salicylates / blood
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Vasodilation / drug effects
  • Vasodilation / physiology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Salicylates
  • NF-KappaB Inhibitor alpha
  • 3-nitrotyrosine
  • Tyrosine
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • salicylsalicylic acid