Homocysteine stimulates nuclear factor kappa B activity and monocyte chemoattractant protein-1 expression in vascular smooth-muscle cells: a possiblerole for protein kinase C

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that stimu lates the migration of monocytes into the intima of arterial walls. Althoug h many factors that induce MCP-1 expression have been identified, the effec t of homocysteine on the expression of MCP-1 in atherogenesis and the under lying mechanisms are not entirely clear. The objective of the present study was to investigate the role of homocysteine in MCP-1 expression in human a orta vascular smooth-muscle cells (VSMCs). After VSMCs were incubated with homocysteine for various time periods, a nuclease protection assay and ELIS A were performed. Homocysteine (0.05-0.2 mM) significantly increased the ex pression of MCP-1 mRNA (up to 2.7-fold) and protein (up to 3.3-fold) in the se cells. The increase in MCP-1 expression was associated with the activati on of protein kinase C (PKC) as well as nuclear factor kappaB (NF-kappaB). Further investigation demonstrated that the activation of NF-kappaB was the result of a PKC-mediated reduction in the expression of inhibitory protein (I kappaB alpha) mRNA and protein in homocysteine-treated cells. Oxidative stress might also be involved in the activation of NF-kappaB by homocystei ne in VSMCs. In conclusion, the present study has clearly demonstrated that the activation of PKC as well as superoxide production followed by activat ion of NF-kappaB is responsible for homocysteine-induced MCP-1 expression i n VSMCs. These results suggest that homocysteine-stimulated MCP-1 expressio n via NF-kappaB activation may play an important role in atherogenesis.