Published online before print November 20, 2003, doi: 10.1161/01.RES.0000108264.67601.2C
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Submitted on April 28, 2003
Revised on October 15, 2003
Accepted on November 3, 2003
Hyperhomocysteinemia Activates Nuclear Factor-
B in Endothelial Cells via Oxidative Stress
Kathy K.W. Au-Yeung ;
From the Department of Pharmacology (F.L.S., J.C.W.Y., Y.L.S., K.O), Faculty of Medicine, The University of Hong Kong, and National Centre for Agri-Food Research in Medicine (K.K.W.A-Y., C.W.H.W., Y.L.S., K.O.), Departments of Animal Science and Physiology, University of Manitoba, Canada.
* To whom correspondence should be addressed. E-mail: karmino{at}sbrc.ca.
Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-
B (NF-B) 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-B activation and the underlying mechanism of Hcy-induced NF-B activation in endothelial cells. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-B and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. The underlying mechanism of Hcy-induced NF-B activation was investigated in human umbilical cord vein endothelial cells and in human aortic endothelial cells. Incubation of cells with Hcy (100 µmol/L) activated IB kinases (IKK
and IKK
), leading to phosphorylation and subsequent degradation of IB. As a consequence, NF-B nuclear translocation, enhanced NF-B/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 IB kinase inhibitor (prostaglandin A1) could prevent Hcy-induced activation of IKK kinases and NF-B in endothelial cells. In conclusion, these results suggest that Hcy-induced superoxide anion production may play a potential role for NF-B activation in the early stages of atherosclerosis in the vascular wall via activation of IB kinases.
Key words: homocysteine • nuclear factor-
B •
IB •
IB kinase •
superoxide
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