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

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Abstract
Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-κB (NF-κB) 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-κB activation and the underlying mechanism of Hcy-induced NF-κB activation in endothelial cells. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-κB and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. The underlying mechanism of Hcy-induced NF-κB 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 IκB kinases (IKKα and IKKβ), leading to phosphorylation and subsequent degradation of IκBα. As a consequence, NF-κB nuclear translocation, enhanced NF-κB/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 IκB kinase inhibitor (prostaglandin A1) could prevent Hcy-induced activation of IKK kinases and NF-κB in endothelial cells. In conclusion, these results suggest that Hcy-induced superoxide anion production may play a potential role for NF-κB activation in the early stages of atherosclerosis in the vascular wall via activation of IκB kinases.