Nafoxidine modulates the expression of matrix-metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in endothelial cells.
During angiogenesis, proteases and their inhibitors interact in the remodelling of the basement membrane. It has been demonstrated that nafoxidine has antiangiogenic activity in the chick egg chorioallantoic membrane assay, but the precise mechanism of action is unknown. We have analyzed the effect of the partial estrogen antagonist nafoxidine on human umbilical vein endothelial cells (HUVEC). Our data indicated that in nafoxidine-treated endothelial cells MMP-2 was activated. Nafoxidine upregulated, in a dose-dependent manner, the secretion of a 66 kDa TIMP-1 dimer, that lacks anti-MMP activity and inhibited angiogenesis in the endothelial cord formation assay. We can postulate that nafoxidine induces an increase in TIMP-1, which has antiangiogenic activity in the late stages of tube formation, independent of its capacity to inhibit MMPs.
De Lorenzo
M S
MS
Department of Science and Technology, Quilmes National University, Buenos Aires, Argentina. mdeloren@ung.edu.ar
Alonso
D F
DF
Gomez
D E
DE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D009256:Nafoxidine / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis* / Q000235:genetics; D014471:Umbilical Veins
D020533:Angiogenesis Inhibitors; D017077:Culture Media, Conditioned; D020847:Estrogen Receptor Modulators; D006133:Growth Substances; D019715:Tissue Inhibitor of Metalloproteinase-1; D009256:Nafoxidine; D020778:Matrix Metalloproteinase 2