Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A pathway.

Details

Serval ID
serval:BIB_29D8613FBC56
Type
Article: article from journal or magazin.
Collection
Publications
Title
Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A pathway.
Journal
Biochemical pharmacology
Author(s)
Giurdanella G., Anfuso C.D., Olivieri M., Lupo G., Caporarello N., Eandi C.M., Drago F., Bucolo C., Salomone S.
ISSN
1873-2968 (Electronic)
ISSN-L
0006-2952
Publication state
Published
Issued date
01/08/2015
Peer-reviewed
Oui
Volume
96
Number
3
Pages
278-287
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Diabetic retinopathy, a major cause of vision loss, is currently treated with anti-VEGF agents. Here we tested two hypotheses: (i) high glucose damages retinal pericytes, the cell layer surrounding endothelial cells, via VEGF induction, which may be counteracted by anti-VEGFs and (ii) activation of PLA2/COX-2 pathway by high glucose might be upstream and/or downstream of VEGF in perycites, as previously observed in endothelial cells. Human retinal pericytes were treated with high glucose (25mM) for 48h and/or anti-VEGFs (40μg/ml aflibercept, 25μg/ml bevacizumab, 10μg/ml ranibizumab). All anti-VEGFs significantly prevented high glucose-induced cell damage (assessed by LDH release) and improved cell viability (assessed by MTT and Evans blue). High glucose-induced VEGF-A expression, as detected both at mRNA (qPCR) and protein (ELISA) level, while receptor (VEGFR1 and VEGFR2) expression, detected in control condition, was unaffected by treatments. High glucose induced also activation of PLA2/COX-2 pathway, as revealed by increased phosphorylation of cPLA2, COX-2 expression and PGE2 release. Treatment with cPLA2 (50μM AACOCF3) and COX-2 (5μM NS-392) inhibitors prevented both cell damage and VEGF-A induced by high glucose. Finally, challenge with exogenous VEGF-A (10ng/ml) induced VEGF-A expression, while anti-VEGFs reduced VEGF-A expression induced by either high glucose or exogenous VEGF-A. These data indicate that high glucose directly damages pericytes through activation of PLA2/COX-2/VEGF-A pathway. Furthermore, a kind of feed-forward loop between cPLA2/COX-2/PG axis and VEGF appears to operate in this system. Thus, anti-VEGFs afford protection of pericytes from high glucose by inhibiting this loop.
Keywords
Angiogenesis Inhibitors/pharmacology, Antibodies, Monoclonal, Humanized/pharmacology, Arachidonic Acids/pharmacology, Bevacizumab, Cell Count, Cell Survival/drug effects, Cyclooxygenase 2/genetics, Cyclooxygenase 2/metabolism, Enzyme Inhibitors/pharmacology, Feedback, Physiological, Gene Expression Regulation, Glucose/antagonists & inhibitors, Glucose/toxicity, Humans, Pericytes/cytology, Pericytes/drug effects, Pericytes/metabolism, Phospholipases A2/genetics, Phospholipases A2/metabolism, Phosphorylation/drug effects, Primary Cell Culture, Ranibizumab, Receptors, Vascular Endothelial Growth Factor/pharmacology, Recombinant Fusion Proteins/pharmacology, Retina/cytology, Retina/drug effects, Retina/metabolism, Signal Transduction, Vascular Endothelial Growth Factor A/genetics, Vascular Endothelial Growth Factor A/metabolism, Vascular Endothelial Growth Factor Receptor-1/genetics, Vascular Endothelial Growth Factor Receptor-1/metabolism, Vascular Endothelial Growth Factor Receptor-2/genetics, Vascular Endothelial Growth Factor Receptor-2/metabolism, Aflibercept, Diabetic retinopathy, VEGF
Pubmed
Web of science
Create date
12/03/2021 18:01
Last modification date
26/03/2021 6:35
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