Regulation of matrix metalloprotcase-9 production induced by monocyte-vascular endothelial cell interaction - role of hepatocyte growth factor and vascular endothelial growth.

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Matrix metalloproteases (MMP) have been shown to play an important role in plaque rupture ; however, the mechanisms that regulate MMP production remain to be determined. In the present study we investigated the effect of monocyte-vascular endothelial cell (EC) interaction on MMP production using human monocyte derived cell line (THP-1) and human umbilical vein endolhelial cells (HUVEC), and. Tested the hypothesis that hepatocyte growth factor (HGF) may regulate MMP production. THP-1 were cocultured with HUVEC or cultured alone in serum-free medium for 16 h. Production of MMP-2, MMP-9, HGF and vascular endothelial growth factor (VEGF) in the medium was examined by ELISA. Anti-HGF neutralizing antibody (HGFAb) and anti-VEGF neutralizing antibody (VEGFAb) were used for blocking studies. MMP-9 production significantly increased in cocultured THP-1 compared to THP-1 alone (92.6 ±4.4 vs 28.4 ± 2.9 ng/ml, n=6 ; p<0.05), whereas MMP-2 production was unchanged. Production of HGF and VEGF also increased in cocultured THP-1 com pared to THP-1 alone (252.0±51.6 vs 182.9±29.5 pg/ml, 277.6±98,9 vs 29.5+4.8 pg/ml, respectively, n=6 ; p<0.05). HGFAb significantly increased MMP-9 production in cocultured THP-1 by 1.7-fold, whereas VEGFAb and control IgG had no effect. These data establish a novel function of HGF in monocyte-EC interaction that inhibits MMP-9 production, indicating a critical role of HGF for plaque stabilization.