Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress

Circ Res. 2004 Jan 9;94(1):28-36. doi: 10.1161/01.RES.0000108264.67601.2C. Epub 2003 Nov 20.

Abstract

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-kappaB (NF-kappaB) activation and homocysteine (Hcy)-induced chemokine expression in vascular smooth muscle cells and macrophages. The objective of the present study was to investigate the in vivo effect of hyperhomocysteinemia on NF-kappaB activation and the underlying mechanism of Hcy-induced NF-kappaB activation in endothelial cells. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-kappaB and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. The underlying mechanism of Hcy-induced NF-kappaB activation was investigated in human umbilical cord vein endothelial cells and in human aortic endothelial cells. Incubation of cells with Hcy (100 micromol/L) activated IkappaB kinases (IKKalpha and IKKbeta), leading to phosphorylation and subsequent degradation of IkappaBalpha. As a consequence, NF-kappaB nuclear translocation, enhanced NF-kappaB/DNA binding activity, and increased transcriptional activity occurred. Additional analysis revealed a marked elevation of superoxide anion levels in Hcy-treated cells. Treatment of cells with a superoxide anion scavenger (polyethylene glycol-superoxide dismutase) or IkappaB kinase inhibitor (prostaglandin A(1)) could prevent Hcy-induced activation of IKK kinases and NF-kappaB in endothelial cells. In conclusion, these results suggest that Hcy-induced superoxide anion production may play a potential role for NF-kappaB activation in the early stages of atherosclerosis in the vascular wall via activation of IkappaB kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / chemistry
  • Aorta / cytology
  • Cells, Cultured
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Homocysteine / pharmacology
  • Hyperhomocysteinemia / metabolism*
  • I-kappa B Kinase
  • I-kappa B Proteins / metabolism
  • Male
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Oxidative Stress*
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Superoxides / analysis
  • Superoxides / metabolism

Substances

  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, rat
  • Homocysteine
  • Superoxides
  • NF-KappaB Inhibitor alpha
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase