Sialic acid containing glycosphingolipids (gangliosides) have been implicated in regulating various biological phenomena such as atherosclerosis. Disialoganglioside (GD3) inhibited DNA synthesis of cultured VSMC in the presence of PDGF with down-regulation of cyclinE/CDK2 and up-regulation of the CDK inhibitor p21 and p27 expression. GD3 inhibited TNF-α-induced matrix metalloproteinase-9 (MMP-9) expression in VSMC and decreased MMP-9 promoter activity in response to TNF-α, which was transcriptionally regulated at NF-ĸB and activation protein-1 (AP-1) sites in the MMP-9 promoter. These suggest that the GD3 represents a physiological modulator of VSMC responses that may contribute to plaque instability in atherosclerosis. On the other hand, pyrrolidine dithiocarbamate (PDTC), a metal chelating antioxidant and pro-oxidant compound reduced cell growth and DNA synthesis on VSMC in low density conditions. However, in serum depleted medium, PDTC did not affect the cell viability. At low VSMC density in 10% FBS, PDTC induced cell cycle arrest in the G1 phase. The cell cycle arrest is associated with the down-regulation of cyclin D1, cyclin E, CDK2, CDK4 and up-regulation of the CDK inhibitor p21 expression. These inhibitory effects were associated with enhanced expression of   p21 and increased complexing of p21 with cyclin D1/CDK4 and cyclin E/CDK2. PDTC induced marked activation of p38MAPK and JNK. SB203580, a p38MAPK specific inhibitor, blocked PDTC-dependent p38MAPK, growth inhibition, and p21 expression. The cells were transfected with antisense-p21 oligodeoxynucleotide also decreased PDTC-induced p38 MAPK activity. These data demonstrate that the p38MAPK pathway participates in p21 induction, leading to decrease of cyclin D1/cdk4 and cyclin E/cdk2 complexes and PDTC-dependent VSMC growth inhibition. Finally, quercetin, a bioflavonoid, is known to inhibit angiotensin II-induced hypertrophy and serum-induced smooth muscle cell proliferation. Treatment of quercetin showed potent inhibitory effects on DNA synthesis of cultured human aortic smooth muscle cells (HASMC) in the presence of TNF-α. These inhibitory effects were associated with reduced extracellular signal-regulated kinase (ERK) 1/2 activity and G1 cell cycle arrest. Quercetin induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression. Quercetin inhibited TNF-α-induced MMP-9 secretion on HASMC in a dose dependent manner by down-regulation of MMP-9, indicating the efficacy of quercetin in inhibiting cell proliferation, G1 to S phase cell cycle progress and MMP-9 expression through the transcription factors NF-kB and AP-1 on TNF-α-induced HASMC.