Survival Signaling in Retinal Pigment Epithelial Cells in Response to Oxidative Stress: Significance in Retinal Degenerations
Photoreceptor survival depends on the integrity of retinal pigment epithelial (RPE) cells. The pathophysiology of several retinal degenerations involves oxidative stress-mediated injury and RPE cell death; in some instances it has been shown that this event is mediated by A2E and its epoxides. Photoreceptor outer segments display the highest DHA content of any cell type. RPE cells are active in DHA uptake, conservation, and delivery. Delivery of DHA to photoreceptor inner segments is mediated by the interphotoreceptor matrix. DHA is necessary for photoreceptor function and at the same time is a target of oxidative stress-mediated lipid peroxidation. It has not been clear whether specific mediators generated from DHA contribute to its biological properties. Using ARPE-19 cells, we demonstrated the synthesis of 10,17S-docosatriene [neuroprotectin D1 (NPD1)]. This synthesis was enhanced by the calcium ionophore A-23187, by IL-1β, or by supplying DHA. Added NPD1 (50nM) potently counteracted H2O2/tumor necrosis factor-α oxidative stress-triggered apoptotic DNA damage in RPE. NPD1 also up-regulated the anti-apoptotic proteins Bcl-2 and Bcl-xL and decreased pro-apoptotic Bax and Bad expression. Moreover, NPD1 (50nM) inhibited oxidative stress-induced caspase-3 activation. NPD1 also inhibited IL-1β-stimulated expression of COX-2. Furthermore, A2E-triggered oxidative stress induction of RPE cell apoptosis was also attenuated by NPD1. Overall, NPD1 protected RPE cells from oxidative stress-induced apoptosis. In conclusion, we have demonstrated an additional function of the RPE: its capacity to synthesize NPD1. This new survival signaling is potentially of interest in the understanding of the pathophysiology of retinal degenerations and in exploration of new therapeutic modalities.
KeywordsRetinal Pigment Epithelial Retinal Pigment Epithelial Cell Outer Segment Retinal Degeneration Docoshexaenoic Acid
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- Aveldano de Caldironi, M. I., and Bazan, N. G., 1977, Acyl groups, molecular species, and labeling by 14C-glycerol and 3H-arachidonic acid of vertebrate retina glycerolipids. Adv. Exp. Med. Biol. 83:249–256.Google Scholar
- Barreiro, S. G., Marcheselli, V. L., and Bazan, N. G., 2005, Human retinal pigment epithelial cells protected by NPD1 after A2E-epoxide induction. ARVO abstract B224.Google Scholar
- Bazan, N. G., 1990, Supply of n-3 polyunsaturated fatty acids and their significance in the central nervous system. Nutrition and the Brain, vol. 8, R. J. Wurtman, and J. J. Wurtman, eds., Raven Press, Ltd., New York, pp. 1–24.Google Scholar
- Bazan, N. G., in press Eicosanoids, docosanoids, platelet-activating factor, and inflammation. Basic Neurochemistry 7th ed. G. Siegel, R. W. Albers, S. Brady, and D. Price, eds. London, Elsevier.Google Scholar
- Bazan, N. G., Birkle, D. L., and Reddy, T. S., 1985, Biochemical and nutritional aspects of the metabolism of polyunsaturated fatty acids and phospholipids in experimental models of retinal degeneration. Retinal Degeneration: Experimental and Clinical Studies. M. M. LaVail, R. E. Anderson, and J. Hollyfield, eds. Alan R. Liss, Inc., New York, pp. 159–187.Google Scholar
- Bazan N. G., Marcheselli, V. L., Hu, J., Finley, J., Bok, D., and Chandamuri, B., 2005, Pigment epithelium-derived growth factor (PEDF) selectively up-regulates NPD1 synthesis and release throught the apical side of human RPE cells in primary cultures. ARVO abstract B141.Google Scholar
- Bryckaert, M., Guillonneau, X., Hecquet, C., Courtois, Y., and Mascarelli, F., 1999, Both FGF1 and bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2. Oncogene. 18:7584–7593.PubMedCrossRefGoogle Scholar
- Marcheselli, V. L. Hong, S., Lukiw, W. J., Tian, X. H., Gronert, K., Musto, A., Hardy, M., Gimenez, J. M., Chiang, N., Serhan, C. N., and Bazan, N. G., 2003, Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278:43807–43817. Erratum in: J. Biol. Chem. 2003, 278:51974.PubMedCrossRefGoogle Scholar
- Mattson, M. P., and Bazan, N. G., in press, Apoptosis and necrosis. Basic Neurochemistry 7th ed. G. Siegel, R. W. Albers, S. Brady, D. Price, eds., London, Elsevier.Google Scholar
- Salem, N. Jr, Kim, H. Y., and Yergey, J. A., 1986, Docoshexaenoic acid: membrane function and metabolism. The Health Effects of Polyunsaturated Fatty Acids in Seafoods, A. P. Simopoulos, R. R. Kifer, and R. Martin, eds., Academic Press, New York, NY, pp. 263–317.Google Scholar
- Sieving, P. A., Chaudhry, P., Kondo, M., Provenzano, M., Wu, D., Carlson, T. J., Bush, R. A., and Thompson, D. A., 2001, Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc. Natl. Acad. Sci. USA 98:1835–1840.PubMedCrossRefGoogle Scholar