Ahmed M Abu El-Asrar1, Kaiser Alam2, Mohd Imtiaz Nawaz2, Ghulam Mohammad2, Kathleen Van den Eynde3, Mohammad Mairaj Siddiquei2, Ahmed Mousa2, Gert De Hertogh3, Karel Geboes3, Ghislain Opdenakker4. 1. Department of Ophthalmology College of Medicine, King Saud University, Riyadh, Saudi Arabia 2Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 2. Department of Ophthalmology College of Medicine, King Saud University, Riyadh, Saudi Arabia. 3. Laboratory of Histochemistry and Cytochemistry, University of Leuven, KU Leuven, Leuven, Belgium. 4. Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
Abstract
PURPOSE: To determine and interrelate the levels of heparanase, syndecan-1, and VEGF in proliferative diabetic retinopathy (PDR), and to study the production of heparanase by human retinal microvascular endothelial cells (HRMEC) and its effect on HRMEC barrier function. METHODS: Vitreous samples from 33 PDR and 27 nondiabetic patients, epiretinal membranes from 16 patients with PDR and HRMEC were studied by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis. The effect of heparanase on HRMEC barrier function was evaluated by transendothelial electrical resistance. RESULTS: We showed a significant increase in the expression of heparanase, syndecan-1, and VEGF in vitreous samples from PDR patients compared with nondiabetic controls (P < 0.0001 for all comparisons). Significant positive correlations were found between the levels of heparanase and the levels of syndecan-1 (r = 0.75, P < 0.0001) and VEGF (r = 0.91, P < 0.0001) and between the levels of syndecan-1 and the levels of VEGF (r = 0.78, P < 0.0001). In epiretinal membranes, heparanase was expressed in vascular endothelial cells and CD45-expressing leukocytes. High-glucose, tumor necrosis factor alpha (TNF-α), and the combination of TNF-α and interleukin (IL)-1β, but not cobalt chloride induced upregulation of heparanase in HRMEC. Heparanase-reduced transendothelial electrical resistance of HRMEC. CONCLUSIONS: Our findings suggest a link between heparanase, syndecan-1, and VEGF in the progression of PDR and that heparanase is a potential target for therapy of diabetic retinopathy.
PURPOSE: To determine and interrelate the levels of heparanase, syndecan-1, and VEGF in proliferative diabetic retinopathy (PDR), and to study the production of heparanase by human retinal microvascular endothelial cells (HRMEC) and its effect on HRMEC barrier function. METHODS: Vitreous samples from 33 PDR and 27 nondiabetic patients, epiretinal membranes from 16 patients with PDR and HRMEC were studied by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis. The effect of heparanase on HRMEC barrier function was evaluated by transendothelial electrical resistance. RESULTS: We showed a significant increase in the expression of heparanase, syndecan-1, and VEGF in vitreous samples from PDR patients compared with nondiabetic controls (P < 0.0001 for all comparisons). Significant positive correlations were found between the levels of heparanase and the levels of syndecan-1 (r = 0.75, P < 0.0001) and VEGF (r = 0.91, P < 0.0001) and between the levels of syndecan-1 and the levels of VEGF (r = 0.78, P < 0.0001). In epiretinal membranes, heparanase was expressed in vascular endothelial cells and CD45-expressing leukocytes. High-glucose, tumor necrosis factor alpha (TNF-α), and the combination of TNF-α and interleukin (IL)-1β, but not cobalt chloride induced upregulation of heparanase in HRMEC. Heparanase-reduced transendothelial electrical resistance of HRMEC. CONCLUSIONS: Our findings suggest a link between heparanase, syndecan-1, and VEGF in the progression of PDR and that heparanase is a potential target for therapy of diabetic retinopathy.
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