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J. M. Calandria, N. G. Bazan; Neuroprotectin D1 Enhances Expression of Genes Related to Stress Response Survival. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3399.
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© ARVO (1962-2015); The Authors (2016-present)
Apoptotic cell death of photoreceptors takes place in neurodegenerative diseases such as retinitis pigmentosa and macular degeneration. Oxidative stress injury triggers apoptotic damage on RPE cells, enhancing the enzymatic production of neuroprotectin D1 (NPD1), a potent neuroprotective lipid mediator, that down-regulates the expression of pro-inflammatory proteins and enhances the expression of the anti-apoptotic Bcl2 family (Bazan NG, 2007. IOVS 48:4866-81), hence promoting cell survival. We hypothesize that NPD1 signaling promotes the transcription modulation of a group of genes that contributes to the homeostatic survival response of the cell to oxidative stress.
An ARPE-19 stably-silenced 15-LOX 1 cell line was used to study the NPD1-dependent modulation of the transcription at 2h and 6h. The oxidative stress-induced expression of the knock-down cells and controls with and without NPD1 (50nM) was assessed by microarray technology; apoptotic ratio was measured with Hoechst staining. Enrichment analysis, used to identify the overrepresentation theme by matching gene IDs for common, similar and unique sets, was applied based on gene IDs in functional ontologies, including canonical pathway maps, Gene Go and GO cellular processes.
More than 300 genes were modulated in response to NPD1 when cells were subjected to oxidative stress. Chemokines such as pro-mitotic CXCL1 were down-regulated by 6 h of oxidative stress and up-regulated by NPD1, and CXCL3 was down-regulated by NPD1. Modulation of the expression of transcriptional regulators was observed. In this latter group we found the NPD1-dependent decreased expression of Ataxin-3 and Bcl6 expression, both repressors of the transcription. MAPK pathway components also were modulated by NPD1. The transcription factor network analysis showed the involvement of NF-kB, c-Jun, STAT1, GCR-alpha and EGR1 in the modulation of gene transcription concerning different cellular processes such as stress and immune response signaling via MAPK, and pro-survival reaction via growth factors.
The data suggests that NPD1 modifies gene expression, enhancing intrinsic pathways related with RPE cell survival regulation.
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