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(Circulation Research. 2004;94:28.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Hyperhomocysteinemia Activates Nuclear Factor-B in Endothelial Cells via Oxidative Stress

Kathy K.W. Au-Yeung, Connie W.H. Woo, Fion L. Sung, Johnny C.W. Yip, Yaw L. Siow, Karmin O

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.

Correspondence to Dr Karmin O, MD, PhD, Laboratory of Integrative Biology, NCARM, St Boniface Hospital Research Centre, R4032, 351 Tache Ave, Winnipeg, Manitoba R2H 2A6, Canada. 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 IKKß), 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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