The chemokine platelet factor-4 variant (PF-4var)/CXCL4L1 inhibits diabetes-induced blood–retinal barrier breakdown

Ahmed M. Abu El-Asrar, Ghulam Mohammad, Mohd Imtiaz Nawaz, Mohammed Abdelsaid, Mohammad Mairaj Siddiquei, Kaiser Alam, Kathleen Van Den Eynde, Gert De Hertogh, Ghislain Opdenakker, Mohamed Al-Shabrawey, Jo Van Damme, Sofie Struyf

Research output: Contribution to journalArticle

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Abstract

PURPOSE. To investigate the expression of platelet factor-4 variant (PF-4var/CXCL4L1) in epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) and the role of PF-4var/CXCL4L1 in the regulation of blood–retinal barrier (BRB) breakdown in diabetic rat retinas and human retinal microvascular endothelial cells (HRMEC). METHODS. Rats were treated intravitreally with PF-4var/CXCL4L1 or the anti-vascular endothelial growth factor (VEGF) agent bevacizumab on the first day after diabetes induction. Blood–retinal barrier breakdown was assessed in vivo with fluorescein isothiocyanate (FITC)-conjugated dextran and in vitro in HRMEC by transendothelial electrical resistance and FITC-conjugated dextran cell permeability assay. Occludin, vascular endothelial (VE)-cadherin, hypoxia-inducible factor (HIF)-1α, VEGF, tumor necrosis factor (TNF)-α, receptor for advanced glycation end products (RAGE), caspase-3 levels, and generation of reactive oxygen species (ROS) were assessed by Western blot, enzyme-linked immunosorbent assays, or spectrophotometry. RESULTS. In epiretinal membranes, vascular endothelial cells and stromal cells expressed PF- 4var/CXCL4L1. In vitro, HRMEC produced PF-4var/CXCL4L1 after stimulation with a combination of interleukin (IL)-1β and TNF-α, and PF-4var/CXCL4L1 inhibited VEGF-mediated hyperpermeability in HRMEC. In rats, PF-4var/CXCL4L1 was as potent as bevacizumab in attenuating diabetes-induced BRB breakdown. This effect was associated with upregulation of occludin and VE-cadherin and downregulation of HIF-1α, VEGF, TNF-α, RAGE, and caspase-3, whereas ROS generation was not altered. CONCLUSIONS. Our findings suggest that increasing the intraocular PF-4var/CXCL4L1 levels early after the onset of diabetes protects against diabetes-induced BRB breakdown.

Original languageEnglish (US)
Pages (from-to)1956-1974
Number of pages19
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number3
DOIs
StatePublished - Feb 24 2015

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Platelet Factor 4
Chemokines
Endothelial Cells
Vascular Endothelial Growth Factor A
Epiretinal Membrane
Occludin
Hypoxia-Inducible Factor 1
Tumor Necrosis Factor Receptors
Caspase 3
Reactive Oxygen Species
Spectrophotometry
Diabetic Retinopathy
Stromal Cells
Electric Impedance
Interleukin-1
Retina
Permeability
Up-Regulation
Down-Regulation
Tumor Necrosis Factor-alpha

Keywords

  • Blood-retinal barrier
  • Diabetic retinopathy
  • Platelet factor-4 variant (PF-4var/CXCL4L1)

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Abu El-Asrar, A. M., Mohammad, G., Nawaz, M. I., Abdelsaid, M., Siddiquei, M. M., Alam, K., ... Struyf, S. (2015). The chemokine platelet factor-4 variant (PF-4var)/CXCL4L1 inhibits diabetes-induced blood–retinal barrier breakdown. Investigative Ophthalmology and Visual Science, 56(3), 1956-1974. https://doi.org/10.1167/iovs.14-16144

The chemokine platelet factor-4 variant (PF-4var)/CXCL4L1 inhibits diabetes-induced blood–retinal barrier breakdown. / Abu El-Asrar, Ahmed M.; Mohammad, Ghulam; Nawaz, Mohd Imtiaz; Abdelsaid, Mohammed; Siddiquei, Mohammad Mairaj; Alam, Kaiser; Van Den Eynde, Kathleen; De Hertogh, Gert; Opdenakker, Ghislain; Al-Shabrawey, Mohamed; Van Damme, Jo; Struyf, Sofie.

In: Investigative Ophthalmology and Visual Science, Vol. 56, No. 3, 24.02.2015, p. 1956-1974.

Research output: Contribution to journalArticle

Abu El-Asrar, AM, Mohammad, G, Nawaz, MI, Abdelsaid, M, Siddiquei, MM, Alam, K, Van Den Eynde, K, De Hertogh, G, Opdenakker, G, Al-Shabrawey, M, Van Damme, J & Struyf, S 2015, 'The chemokine platelet factor-4 variant (PF-4var)/CXCL4L1 inhibits diabetes-induced blood–retinal barrier breakdown', Investigative Ophthalmology and Visual Science, vol. 56, no. 3, pp. 1956-1974. https://doi.org/10.1167/iovs.14-16144
Abu El-Asrar, Ahmed M. ; Mohammad, Ghulam ; Nawaz, Mohd Imtiaz ; Abdelsaid, Mohammed ; Siddiquei, Mohammad Mairaj ; Alam, Kaiser ; Van Den Eynde, Kathleen ; De Hertogh, Gert ; Opdenakker, Ghislain ; Al-Shabrawey, Mohamed ; Van Damme, Jo ; Struyf, Sofie. / The chemokine platelet factor-4 variant (PF-4var)/CXCL4L1 inhibits diabetes-induced blood–retinal barrier breakdown. In: Investigative Ophthalmology and Visual Science. 2015 ; Vol. 56, No. 3. pp. 1956-1974.
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AU - Nawaz, Mohd Imtiaz

AU - Abdelsaid, Mohammed

AU - Siddiquei, Mohammad Mairaj

AU - Alam, Kaiser

AU - Van Den Eynde, Kathleen

AU - De Hertogh, Gert

AU - Opdenakker, Ghislain

AU - Al-Shabrawey, Mohamed

AU - Van Damme, Jo

AU - Struyf, Sofie

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N2 - PURPOSE. To investigate the expression of platelet factor-4 variant (PF-4var/CXCL4L1) in epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) and the role of PF-4var/CXCL4L1 in the regulation of blood–retinal barrier (BRB) breakdown in diabetic rat retinas and human retinal microvascular endothelial cells (HRMEC). METHODS. Rats were treated intravitreally with PF-4var/CXCL4L1 or the anti-vascular endothelial growth factor (VEGF) agent bevacizumab on the first day after diabetes induction. Blood–retinal barrier breakdown was assessed in vivo with fluorescein isothiocyanate (FITC)-conjugated dextran and in vitro in HRMEC by transendothelial electrical resistance and FITC-conjugated dextran cell permeability assay. Occludin, vascular endothelial (VE)-cadherin, hypoxia-inducible factor (HIF)-1α, VEGF, tumor necrosis factor (TNF)-α, receptor for advanced glycation end products (RAGE), caspase-3 levels, and generation of reactive oxygen species (ROS) were assessed by Western blot, enzyme-linked immunosorbent assays, or spectrophotometry. RESULTS. In epiretinal membranes, vascular endothelial cells and stromal cells expressed PF- 4var/CXCL4L1. In vitro, HRMEC produced PF-4var/CXCL4L1 after stimulation with a combination of interleukin (IL)-1β and TNF-α, and PF-4var/CXCL4L1 inhibited VEGF-mediated hyperpermeability in HRMEC. In rats, PF-4var/CXCL4L1 was as potent as bevacizumab in attenuating diabetes-induced BRB breakdown. This effect was associated with upregulation of occludin and VE-cadherin and downregulation of HIF-1α, VEGF, TNF-α, RAGE, and caspase-3, whereas ROS generation was not altered. CONCLUSIONS. Our findings suggest that increasing the intraocular PF-4var/CXCL4L1 levels early after the onset of diabetes protects against diabetes-induced BRB breakdown.

AB - PURPOSE. To investigate the expression of platelet factor-4 variant (PF-4var/CXCL4L1) in epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) and the role of PF-4var/CXCL4L1 in the regulation of blood–retinal barrier (BRB) breakdown in diabetic rat retinas and human retinal microvascular endothelial cells (HRMEC). METHODS. Rats were treated intravitreally with PF-4var/CXCL4L1 or the anti-vascular endothelial growth factor (VEGF) agent bevacizumab on the first day after diabetes induction. Blood–retinal barrier breakdown was assessed in vivo with fluorescein isothiocyanate (FITC)-conjugated dextran and in vitro in HRMEC by transendothelial electrical resistance and FITC-conjugated dextran cell permeability assay. Occludin, vascular endothelial (VE)-cadherin, hypoxia-inducible factor (HIF)-1α, VEGF, tumor necrosis factor (TNF)-α, receptor for advanced glycation end products (RAGE), caspase-3 levels, and generation of reactive oxygen species (ROS) were assessed by Western blot, enzyme-linked immunosorbent assays, or spectrophotometry. RESULTS. In epiretinal membranes, vascular endothelial cells and stromal cells expressed PF- 4var/CXCL4L1. In vitro, HRMEC produced PF-4var/CXCL4L1 after stimulation with a combination of interleukin (IL)-1β and TNF-α, and PF-4var/CXCL4L1 inhibited VEGF-mediated hyperpermeability in HRMEC. In rats, PF-4var/CXCL4L1 was as potent as bevacizumab in attenuating diabetes-induced BRB breakdown. This effect was associated with upregulation of occludin and VE-cadherin and downregulation of HIF-1α, VEGF, TNF-α, RAGE, and caspase-3, whereas ROS generation was not altered. CONCLUSIONS. Our findings suggest that increasing the intraocular PF-4var/CXCL4L1 levels early after the onset of diabetes protects against diabetes-induced BRB breakdown.

KW - Blood-retinal barrier

KW - Diabetic retinopathy

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