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M. Opreanu, T. A. Lydic, W. J. Esselman, J. V. Busik; Docosahexaenoic Acid (DHA 22:6n3) Inhibits Sphingomyelin Signaling Pathway and Ceramide Production in the Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):45.
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We have previously demonstrated that docosahexaenoic acid is reduced in diabetic retina. DHA has an anti-inflammatory effect on primary human retinal vascular endothelial (hRVE) cells by modifying the composition and signaling of caveolae/lipid rafts. Ceramides, components of lipid rafts, are generated from sphingomyelin by the action of neutral or acid sphingomyelinase or by de novo synthesis. In the vascular system, ceramides appear to regulate both apoptosis and inflammation. The purpose of this study was to determine the effect of treatment with n3 and n6 polyunsaturated fatty acids on sphingomyelinase activity and ceramide production in both cell culture and diabetic retinopathy animal models.
Acid and neutral sphingomyelinase (SMase) activity was determined by sphingomyelinase assay. Desipramine and GW4869 were used to inhibit acid and neutral SMase respectively. Ceramide production was assessed by immunofluorescence. The expression levels of ICAM-1 and VCAM-1 were analyzed by Western Blotting. Lipids extracted from diabetic and control rat retinas were assayed by electrospray ionization mass spectrometry (MS) and MS/MS.
hRVE cells treated with DHA exhibited a 2 fold decrease in acid sphingomyelinase activity and 1.4 fold decrease in neutral sphingomyelinase activity compared to control. Inhibition of acid or neutral SMase significantly reduced the TNF induced adhesion molecule expression. Ceramide production was decreased 1.7 fold in DHA treated and increased 1.3 fold in palmitic acid (16:0) treated hRVE cells compared to control. Mass spectrometry analysis of lipids extracted from rat retinas showed a 44 % increase in 16:0-ceramide in diabetic retinas versus control.
The data is consistent with the hypothesis that DHA exerts its anti-inflammatory effect by modulating sphingomyelin signaling pathways. DHA deficiency in diabetic retinas could thus contribute to a pro-inflammatory state through activation of sphingomyelinase activity and increased ceramide production.
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