A novel function of benzyl isothiocyanate in vascular smooth muscle cells: The role of ERK1/2, cell cycle regulation, and matrix metalloproteinase-9

Dietary isothiocyanates (ITCs) have shown protective effects against certain chemically induced cancers in animal models. These inhibitory effects are associated with reduced levels of extracellular signal-regulated kinase (ERK) 1/2 activity and the arrest of the G, cell cycle. Benzyl isothiocyanate (BITC) treatment down-regulates cyclins and CDKs and Lip-regulates the expression of the CDK inhibitor p21, but up-regulation of p27 or p53 was not detected. Since antiatherogenic effects are not needed for antiproliferation, we determined whether BITC exerted inhibitory effects on matrix metalloproteinase-9 (MMP-9) activity in TNF alpha-induced vascular smooth Muscle cells (VSMCs). BITC inhibited TNF-alpha-included MMP-9 secretion in VSMC in a dose dependent manner. This inhibition was characterized by the down-regulation of MMP-9, which is transcriptionally regulated at the NF-kappa B site, and the activation protein-1 (AP-1) site in the MMP-9 promoter. These findings indicate that BITC is an effective agent for inhibiting cell proliferation, the G, to S phase cell cycle progress, and MMP-9 expression through the transcription factors NF-kappa B and AP-1 in TNF-alpha-inducecl VSMC. (c) 2004 Wiley-Liss, Inc.