Abstract
We have previously shown that intravitreal injection of plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibits ischemia-induced retinal neovascularization in a rat model. Here we report that K5 down-regulates an endogenous angiogenic stimulator, vascular endothelial growth factor (VEGF) and up-regulates an angiogenic inhibitor, pigment epithelium-derived factor (PEDF) in a dose-dependent manner in vascular cells and in the retina. The regulation of VEGF and PEDF by K5 in the retina correlates with its anti-angiogenic effect in a rat model of ischemia-induced retinopathy. Retinal RNA levels of VEGF and PEDF are also changed by K5. K5 inhibits the p42/p44 MAP kinase activation and nuclear translocation of hypoxia-inducible factor-1alpha, which may be responsible for the down-regulation of VEGF. Down-regulation of endogenous angiogenic stimulators and up-regulation of endogenous angiogenic inhibitors, thus leading toward restoration of the balance in angiogenic control, may represent a mechanism for the anti-angiogenic activity of K5.
Publication types
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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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Active Transport, Cell Nucleus / drug effects
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Angiogenesis Inhibitors / pharmacology*
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Down-Regulation
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Endothelial Growth Factors / antagonists & inhibitors*
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Endothelial Growth Factors / genetics
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Eye Proteins*
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Hypoxia-Inducible Factor 1, alpha Subunit
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Kringles
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Lymphokines / antagonists & inhibitors*
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Lymphokines / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Nerve Growth Factors*
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Phosphorylation
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Plasminogen / pharmacology*
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Protein Biosynthesis*
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Proteins / genetics
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RNA, Messenger / analysis
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Retina / metabolism
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Retinal Neovascularization
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Serpins / biosynthesis*
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Serpins / genetics
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Transcription Factors / metabolism
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Up-Regulation
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Angiogenesis Inhibitors
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Endothelial Growth Factors
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Eye Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lymphokines
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Nerve Growth Factors
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Proteins
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RNA, Messenger
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Serpins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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pigment epithelium-derived factor
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Plasminogen
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Mitogen-Activated Protein Kinases