Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom;
Paul
P
Canning
Department of Cell Biology, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom;
Bridget-Ann
BA
Kenny
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom;
Vivien
V
Prise
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom;
Josephine
J
Glenn
Department of Cell Biology, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom; School of Science & Engineering, Teesside University, Middlesbrough TS1 3BA, United Kingdom;
Mosharraf H
MH
Sarker
Department of Cell Biology, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom;
Natalie
N
Hudson
Platform Technology Sciences, GlaxoSmithKline, King of Prussia, PA 19406;
Martin
M
Brandt
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA 19406;
Francisco J
FJ
Lopez
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA 19406;
David
D
Gale
Department of Cell Biology, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom;
Philip J
PJ
Luthert
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom; Ocular Biology and Therapeutics, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom.
Peter
P
Adamson
Department of Cell Biology, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom; a.stitt@qub.ac.uk p.turowski@ucl.ac.uk.
Patric
P
Turowski
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom; a.stitt@qub.ac.uk p.turowski@ucl.ac.uk.
Alan W
AW
Stitt
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001813:Blood-Retinal Barrier / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D008297:Male; D010539:Permeability; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D011914:Rats, Inbred BN; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001713:Biphenyl Compounds; D011744:Pyrimidinones; D042461:Vascular Endothelial Growth Factor A; C470971:SB-435495; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase
VEGF signaling; blood–retinal barrier; diabetic retinopathy; lipoprotein-associated phospholipase A2; lysophosphatidylcholine