Abstract
Angiostatin, a cleavage product of plasminogen, has been shown to inhibit endothelial cell proliferation and metastatic tumor cell growth. Recently, the production of angiostatin has been correlated with tumor-associated macrophage production of elastolytic metalloproteinases in a murine model of Lewis lung cell carcinoma. In this report we demonstrate that purified murine and human matrix metalloproteinases generate biologically functional angiostatin from plasminogen. Macrophage elastase (MMP-12 or MME) proved to be the most efficient angiostatin-producing MMP. MME was followed by gelatinases and then the stomelysins in catalytic efficiency; interstitial collagenases had little capacity to generate angiostatin. Both recombinant angiostatin and angiostatin generated from recombinant MME-treated plasminogen inhibited human microvascular endothelial cell proliferation and differentiation in vitro. Finally, employing macrophages isolated from MME-deficient mice and their wild-type littermates, we demonstrate that MME is required for the generation of angiostatin that inhibits the proliferation of human microvascular endothelial cells.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amides / pharmacology
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Angiostatins
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Animals
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Cells, Cultured
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Culture Media, Conditioned / pharmacology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Fibroblast Growth Factor 2 / pharmacology
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Gelatinases / pharmacology
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Gene Expression Regulation / drug effects*
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Humans
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Macrophages, Peritoneal / metabolism
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Matrix Metalloproteinase 12
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Matrix Metalloproteinase 3 / pharmacology
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / deficiency
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Metalloendopeptidases / genetics
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Metalloendopeptidases / pharmacology*
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Mice
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Mice, Knockout
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Neovascularization, Physiologic / drug effects*
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Peptide Fragments / biosynthesis*
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Peptide Fragments / genetics
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Plasminogen / biosynthesis*
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Plasminogen / drug effects
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Plasminogen / genetics
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Plasminogen / metabolism
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Plasminogen / pharmacology
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Protease Inhibitors / pharmacology
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Tyrosine / analogs & derivatives
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Tyrosine / pharmacology
Substances
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Amides
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Culture Media, Conditioned
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Peptide Fragments
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Protease Inhibitors
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Recombinant Fusion Proteins
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Fibroblast Growth Factor 2
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N-(2-isobutyl-3-(N'-hydroxycarbonylamido)propanoyl)-O-methyltyrosinemethylamide
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Tyrosine
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Angiostatins
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Plasminogen
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Gelatinases
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Metalloendopeptidases
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Matrix Metalloproteinase 3
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MMP12 protein, human
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Matrix Metalloproteinase 12