Canning, P;
Kenny, BA;
Prise, V;
Glenn, J;
Sarker, MH;
Hudson, N;
Brandt, M;
... Stitt, AW; + view all
(2016)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes.
Proceedings of the National Academy of Sciences of the United States of America
, 113
(26)
pp. 7213-7218.
10.1073/pnas.1514213113.
Preview |
Text
PNAS Canning et al June2016.pdf - Accepted Version Download (929kB) | Preview |
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). 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.
| Type: | Article |
|---|---|
| Title: | Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1514213113 |
| Publisher version: | http://dx.doi.org/10.1073/pnas.1514213113 |
| Language: | English |
| Additional information: | Copyright © 2016 National Academy of Sciences. This is the accepted manuscript version of this article; the final published version can be found on the PNAS website at http://www.pnas.org/content/113/26/7213 |
| Keywords: | diabetic retinopathy; VEGF signaling; lysophosphatidylcholine; blood–retinal barrier; lipoprotein-associated phospholipase A2 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1503325 |
Archive Staff Only
 |
View Item |
