2. Academic Validation
  3. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

  • Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7213-8. doi: 10.1073/pnas.1514213113.
Paul Canning 1,  Bridget-Ann Kenny 2,  Vivien Prise 1,  Josephine Glenn 1,  Mosharraf H Sarker 3,  Natalie Hudson 2,  Martin Brandt 4,  Francisco J Lopez 5,  David Gale 5,  Philip J Luthert 2,  Peter Adamson 6,  Patric Turowski 7,  Alan W Stitt 8
Affiliations

Affiliations

  • 1 Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom;
  • 2 Department of Cell Biology, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom;
  • 3 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;
  • 4 Platform Technology Sciences, GlaxoSmithKline, King of Prussia, PA 19406;
  • 5 Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA 19406;
  • 6 Ophthalmology Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom; Ocular Biology and Therapeutics, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom.
  • 7 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.
  • 8 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.
PMID: 27298369 DOI: 10.1073/pnas.1514213113
Abstract

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/KDR/Flk-1). 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/KDR/Flk-1. 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.

Keywords

VEGF signaling; blood–retinal barrier; diabetic retinopathy; lipoprotein-associated phospholipase A2; lysophosphatidylcholine.

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