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J. Biol. Chem., Vol. 277, Issue 11, 9492-9497, March 15, 2002
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From the Department of Ophthalmology, Medical University of South
Carolina, Charleston, South Carolina 29403
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-1
Down-regulation of Vascular Endothelial Growth Factor and
Up-regulation of Pigment Epithelium-derived Factor
A POSSIBLE MECHANISM FOR THE ANTI-ANGIOGENIC ACTIVITY OF
PLASMINOGEN KRINGLE 5*
, 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.
*
This work was supported by National Institutes of Health
Grants EY12600 and EY12231 (to J-x. M.) and EY09741 (to C. E. C.), a research grant from Juvenile Diabetes Foundation
International, a grant from American Diabetes Association (to
J-x. M.), and an unrestricted grant to the Department of Ophthalmology,
Medical University of South Carolina, from Research to
Prevent Blindness, Inc.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Ophthalmology, Medical University of South Carolina, 167 Ashley Ave., Charleston, SC 29403. Tel.: 843-792-9180; Fax: 843-792-1723; E-mail: majx@musc.edu.
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