Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B.
We have studied mechanisms controlling activation of the gelatinase B gene (matrix metalloproteinase-9) by fibroblast growth factor-2 (FGF-2) during angiogenesis, and the effects of the natural product curcuminoids on this process. Using a transgenic mouse (line 3445) harboring a gelatinase B promoter/lacZ fusion gene, we demonstrate FGF-2 stimulation of reporter gene expression in endothelial cells of invading neocapillaries in the corneal micropocket assay. Using cultured corneal cells, we show that FGF-2 stimulates DNA binding activity of transcription factor AP-1 but not NF-kappaB and that AP-1 stimulation is inhibited by curcuminoids. We further show that induction of gelatinase B transcriptional promoter activity in response to FGF-2 is dependent on AP-1 but not NF-kappaB response elements and that promoter activity is also inhibited by curcuminoids. In rabbit corneas, the angiogenic response induced by implantation of an FGF-2 pellet is inhibited by the co-implantation of a curcuminoid pellet, and this correlates with inhibition of endogenous gelatinase B expression induced by FGF-2. Angiostatic efficacy in the cornea is also observed when curcuminoids are provided to mice in the diet. Our findings provide evidence that curcuminoids target the FGF-2 angiogenic signaling pathway and inhibit expression of gelatinase B in the angiogenic process.
Mohan
R
R
Vision Research Laboratories of New England Eye Center and the Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Sivak
J
J
Ashton
P
P
Russo
L A
LA
Pham
B Q
BQ
Kasahara
N
N
Raizman
M B
MB
Fini
M E
ME
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply*; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D004032:Diet; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics
D020533:Angiogenesis Inhibitors; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D016222:Fibroblast Growth Factor 2; D001616:beta-Galactosidase; D020780:Matrix Metalloproteinase 9; D003474:Curcumin