The ganglioside-specific sialidase Neu3 has been suggested to participate in cell growth; migration, and differentiation. Recent reports suggest that sialidase may be involved in intimal thickening, an early stage in the development of atherosclerosis. However, the role of the Neu3 gene in vascular smooth muscle cells (VSMC) responses has not yet been elucidated. To determine whether a Neu3 is able to modulate VSMC growth, the effect of overexpression of the Neu3 gene on cell proliferation was examined. However, the results show that the overexpression of this gene has no effect on DNA synthesis and ERK phosphorylation in cultured VSMC in the presence of TNF-alpha. Because atherogenic effects need not be limited to proliferation, we decided to examine whether Neu3 exerted inhibitory effects on matrix metalloproteinase-9 (NIMP-9) activity in TNF-alpha-induced VSMC. The expression of the Neu3 gene led to the inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by zymography and immunoblot. Furthermore, Neu3 gene expression strongly decreased MMP-9 promoter activity in response to TNF-alpha. This inhibition was characterized by the down-regulation of MMP-9, which was transcriptionally regulated at NF-kappa B and activation protein-I (AP-1) sites in the MMP-9 promoter. These findings suggest that the Neu3 gene represents a physiological modulator of VSMC responses that may contribute to plaque instability in atherosclerosis. (c) 2007 Elsevier Inc. All rights reserved.