High-glucose-induced endothelial cell injury is inhibited by a Peptide derived from human apolipoprotein E

Although the importance of human apolipoprotein E (apoE) in vascular diseases has clearly been established, most of the research on apoE has focused on its role in cholesterol metabolism. In view of the observation that apoE and its functional domains impact extracellular matrix (ECM) remodeling, we...

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Bibliographic Details
Published in:PloS one 2012-12, Vol.7 (12), p.e52152-e52152
Main Authors: Bhattacharjee, Partha S, Huq, Tashfin S, Potter, Valencia, Young, Anna, Davenport, Ian R, Graves, Richard, Mandal, Tarun K, Clement, Christian, McFerrin, Harris E, Muniruzzaman, Syed, Ireland, Shubha K, Hill, James M
Format: Article
Language:English
Subjects:
Analysis
Angiogenesis
Animals
Apolipoprotein E
Apolipoproteins
Apolipoproteins E - chemistry
Biology
Cell injury
Cholesterol
Degradation
Deregulation
Diabetes
Diabetes mellitus
Diabetic retinopathy
Edema
Endothelial cells
Endothelial Cells - cytology
Endothelial Cells - drug effects
Endothelium
Enzymes
Extracellular matrix
Extracellular Matrix - metabolism
Eye
Eye injuries
Glucose
Glucose - pharmacology
Growth factors
Health sciences
Heparan sulfate
Hyperglycemia
In vivo methods and tests
Kinases
Lipid metabolism
Low density lipoprotein
Low Density Lipoprotein Receptor-Related Protein-1 - metabolism
Low density lipoprotein receptors
Low density lipoproteins
Medicine
Metabolism
Mice
Peptides
Peptides - chemistry
Peptides - pharmacology
Permeability
Pharmacy
Physiological aspects
Proteins
Receptor density
Retina
Retina - cytology
Retinopathy
Shedding
Streptozocin
Sulfates
Tight Junction Proteins - metabolism
Vascular diseases
Vascular Endothelial Growth Factor A - metabolism
Zonula occludens-1 protein
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Summary:Although the importance of human apolipoprotein E (apoE) in vascular diseases has clearly been established, most of the research on apoE has focused on its role in cholesterol metabolism. In view of the observation that apoE and its functional domains impact extracellular matrix (ECM) remodeling, we hypothesized that apoE could also confer protection against ECM degradation by mechanisms independent of its role in cholesterol and lipoprotein transport. The ECM degrading enzyme, heparanase, is secreted by cells as pro-heparanase that is internalized through low-density lipoprotein (LDL) receptor-related protein-1 (LRP-1) to become enzymatically active. Both apoE and pro-heparanase bind the LRP-1. We further hypothesized that an apoE mimetic peptide (apoEdp) would inhibit the production of active heparanase by blocking LRP-1-mediated uptake of pro-heparanase and thereby decrease degradation of the ECM. To test this hypothesis, we induced the expression of heparanase by incubating human retinal endothelial cells (hRECs) with high glucose (30 mM) for 72 hours. We found that elevated expression of heparanase by high glucose was associated with increased shedding of heparan sulfate (ΔHS) and the tight junction protein occludin. Treatment of hRECs with 100 µM apoEdp in the presence of high glucose significantly reduced the expression of heparanase, shedding of ΔHS, and loss of occludin as detected by Western blot analysis. Either eye drop treatment of 1% apoEdp topically 4 times a day for 14 consecutive days or intraperitoneal injection (40 mg/kg) of apoEdp daily for 14 consecutive days in an in vivo mouse model of streptozotocin-induced diabetes inhibited the loss of tight junction proteins occludin and zona occludin- 1 (ZO-1). These findings imply a functional relationship between apoE and endothelial cell matrix because the deregulation of these molecules can be inhibited by a short peptide derived from the receptor-binding region of apoE. Thus, strategies targeting ECM-degrading enzymes could be therapeutically beneficial for treating diabetic retinopathy.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0052152