title: Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.
abstract: Docosahexaenoic acid (DHA) is a lipid peroxidation target in oxidative injury to retinal pigment epithelium (RPE) and retina. Photoreceptor and synaptic membranes share the highest content of DHA of all cell membranes. This fatty acid is required for RPE functional integrity; however, it is not known whether specific mediators generated from DHA contribute to its biological significance. We used human ARPE-19 cells and demonstrated the synthesis of 10,17S-docosatriene [neuroprotectin D1 (NPD1)]. This synthesis was enhanced by the calcium ionophore A-23187, by IL-1beta, or by supplying DHA. Under these conditions, there is a time-dependent release of endogenous free DHA followed by NPD1 formation, suggesting that phospholipase A(2) releases the mediator's precursor. Added NPD1 potently counteracted H(2)O(2)/tumor necrosis factor alpha oxidative-stress-triggered apoptotic RPE DNA damage. NPD1 also up-regulated the antiapoptotic proteins Bcl-2 and Bcl-x(L) and decreased proapoptotic Bax and Bad expression. Moreover, NPD1 (50 nM) inhibited oxidative-stress-induced caspase-3 activation. NPD1 also inhibited IL-1beta-stimulated expression of cyclooxygenase 2 promoter transfected into ARPE-19 cells. Overall, NPD1 protected RPE cells from oxidative-stress-induced apoptosis, and we predict that it will similarly protect neurons. This lipid mediator therefore may indirectly contribute to photoreceptor cell survival as well. Because both RPE and photoreceptor cells die in retinal degenerations, our findings contribute to the understanding of retinal cell survival signaling and potentially to the development of new therapeutic strategies.
authors.affiliation: Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Pranab K
authors.initials: PK
authors.lastname: Mukherjee
authors.forename: Victor L
authors.initials: VL
authors.lastname: Marcheselli
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
mesh_terms: D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2; D053938:DNA Fragmentation; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D015227:Lipid Peroxidation; D008565:Membrane Proteins; D015394:Molecular Structure; D018384:Oxidative Stress; D010857:Pigment Epithelium of Eye / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C487679:protectin D1; D004281:Docosahexaenoic Acids; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases