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The migration of vascular smooth muscle cells (VSMCs) into the intima, an important step in injury-induced neointimal hyperplasia, requires the activation of nuclear factor-κB (NF-κB) and the consequent up-regulation of matrix metallopro-teinase-9 (MMP-9). This study was undertaken to test for a possible effect of α-lipoic acid (ALA), a potent inhibitor of NF-.B, on MMP-9 expression. ALA inhibited high-glucose- and TNF-α-stimulated VSMC migrations in vitro. It also inhibited high-glucose- and TNF-α-induced increases in MMP-9 expression. The activity of MMP-9-promoter constructs with mutations in the NF-κB binding site was not inhibited by ALA, indicating an involvement of the NF-κB signaling pathway in the AL A-specific inhibition of MMP-9. These data suggest the possibility that ALA may be useful for the prevention of neointimal hyper-plasia after angioplasty, by inhibiting the NF-κB/ MMP-9 pathway, especially with hyperglycemia.