[PMID]: | 28351645 |
[Au] Autor: | Ibrahim AS; Saleh H; El-Shafey M; Hussein KA; El-Masry K; Baban B; Sheibani N; Wang MH; Tawfik A; Al-Shabrawey M |
[Ad] Endereço: | Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA; Department of Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA; Department of Biochemistry and Clinical Biochemistry, Fa |
[Ti] Título: | Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis. |
[So] Source: | Biochim Biophys Acta;1862(6):636-645, 2017 06. |
[Is] ISSN: | 0006-3002 |
[Cp] País de publicação: | Netherlands |
[La] Idioma: | eng |
[Ab] Resumo: | AIMS: Our previous studies have established a role for 12/15-lipoxygenase (LO) in mediating the inflammatory response in diabetic retinopathy (DR). However, the extent at which the local or systemic induction of 12/15-LO activity involved is unclear. Thus, the current study aimed to characterize the relative contribution of retinal endothelial versus monocytic/macrophagic 12/15-LO to inflammatory responses in DR. MATERIALS & METHODS: We first generated a clustered heat map for circulating bioactive lipid metabolites in the plasma of streptozotocin (STZ)-induced diabetic mice using liquid chromatography coupled with mass-spectrometry (LC-MS) to evaluate changes in circulating 12/15-LO activity. This was followed by comparing the in vitro mouse endothelium-leukocytes interaction between leukocytes isolated from 12/15-LO knockout (KO) versus those isolated from wild type (WT) mice using the myeloperoxidase (MPO) assay. Finally, we examined the effects of knocking down or inhibiting endothelial 12/15-LO on diabetes-induced endothelial cell activation and ICAM-1 expression. RESULTS: Analysis of plasma bioactive lipids' heat map revealed that the activity of circulating 12/15-LO was not altered by diabetes as evident by no significant changes in the plasma levels of major metabolites derived from 12/15-lipoxygenation of different PUFAs, including linoleic acid (13-HODE), arachidonic acid (12- and 15- HETEs), eicosapentaenoic acid (12- and 15- HEPEs), or docosahexaenoic acid (17-HDoHE). Moreover, leukocytes from 12/15-LO KO mice displayed a similar increase in adhesion to high glucose (HG)-activated endothelial cells as do leukocytes from WT mice. Furthermore, abundant proteins of 12-LO and 15-LO were detected in human retinal endothelial cells (HRECs), while it was undetected (15-LO) or hardly detectable (12-LO) in human monocyte-like U937 cells. Inhibition or knock down of endothelial 12/15-LO in HRECs blocked HG-induced expression of ICAM-1, a well-known identified important molecule for leukocyte adhesion in DR. CONCLUSION: Our data support that endothelial, rather than monocytic/macrophagic, 12/15-LO has a critical role in hyperglycemia-induced ICAM-1 expression, leukocyte adhesion, and subsequent local retinal barrier dysfunction. This may facilitate the development of more precisely targeted treatment strategies for DR. |
[Mh] Termos MeSH primário: |
Araquidonato 12-Lipoxigenase/metabolismo Araquidonato 15-Lipoxigenase/metabolismo Retinopatia Diabética/enzimologia Células Endoteliais/enzimologia Leucostasia/enzimologia Macrófagos/enzimologia Monócitos/enzimologia Retina/enzimologia
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[Mh] Termos MeSH secundário: |
Animais Araquidonato 12-Lipoxigenase/genética Araquidonato 15-Lipoxigenase/genética Adesão Celular/genética Retinopatia Diabética/genética Retinopatia Diabética/patologia Células Endoteliais/patologia Seres Humanos Molécula 1 de Adesão Intercelular/biossíntese Molécula 1 de Adesão Intercelular/genética Leucostasia/genética Leucostasia/patologia Macrófagos/patologia Camundongos Camundongos Knockout Monócitos/patologia Retina/patologia Células U937
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (12-15-lipoxygenase); 0 (Icam1 protein, mouse); 126547-89-5 (Intercellular Adhesion Molecule-1); EC 1.13.11.31 (Arachidonate 12-Lipoxygenase); EC 1.13.11.33 (Arachidonate 15-Lipoxygenase) |
[Em] Mês de entrada: | 1708 |
[Cu] Atualização por classe: | 170814 |
[Lr] Data última revisão:
| 170814 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170330 |
[St] Status: | MEDLINE |
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