About this Journal Submit a Manuscript Table of Contents
Journal of Biomedicine and Biotechnology
Volume 2012 (2012), Article ID 580687, 8 pages
http://dx.doi.org/10.1155/2012/580687
Review Article

PEDF in Diabetic Retinopathy: A Protective Effect of Oxidative Stress

Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China

Received 8 December 2011; Accepted 8 February 2012

Academic Editor: Takeshi Yabe

Copyright © 2012 Xiao-feng Zhu and Hai-dong Zou. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. Resnikoff, D. Pascolini, D. Etya'ale et al., “Global data on visual impairment in the year 2002,” Bulletin of the World Health Organization, vol. 82, no. 11, pp. 844–851, 2004. View at Scopus
  2. J. H. Kempen, B. J. O'Colmain, M. C. Leske, et al., “Eye diseases prevalence research group. The prevalence of diabetic retinopathy among adults in the United States,” Archives of Ophthalmology, vol. 122, no. 4, pp. 552–563, 2004.
  3. J. B. Saaddine, A. A. Honeycutt, K. M. V. Narayan, X. Zhang, R. Klein, and J. P. Boyle, “Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus: United States, 2005–2050,” Archives of Ophthalmology, vol. 126, no. 12, pp. 1740–1747, 2008. View at Publisher · View at Google Scholar · View at Scopus
  4. American Diabetes Association, “Standards of medical care in diabetes—2007,” Diabetes Care, vol. 30, supplement 1, pp. S4–S41, 2007. View at Publisher · View at Google Scholar
  5. H. Shamoon, H. Duffy, N. Fleischer et al., “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,” New England Journal of Medicine, vol. 329, no. 14, pp. 977–986, 1993. View at Publisher · View at Google Scholar
  6. R. A. Kowluru, M. Kanwar, and A. Kennedy, “Metabolic memory phenomenon and accumulation of peroxynitrite in retinal capillaries,” Experimental Diabesity Research, vol. 2007, Article ID 21976, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. P. S. Chan, M. Kanwar, and R. A. Kowluru, “Resistance of retinal inflammatory mediators to suppress after reinstitution of good glycemic control: novel mechanism for metabolic memory,” Journal of Diabetes and its Complications, vol. 24, no. 1, pp. 55–63, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. R. A. Kowluru, “Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats,” Diabetes, vol. 52, no. 3, pp. 818–823, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. K. Naruse, J. Nakamura, Y. Hamada et al., “Aldose reductase inhibition prevents glucose-induced apoptosis in cultured bovine retinal microvascular pericytes,” Experimental Eye Research, vol. 71, no. 3, pp. 309–315, 2000. View at Publisher · View at Google Scholar · View at Scopus
  10. P. Geraldes, J. Hiraoka-Yamamoto, M. Matsumoto et al., “Activation of PKC-and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy,” Nature Medicine, vol. 15, no. 11, pp. 1298–1306, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. T. C. B. Moore, J. E. Moore, Y. Kaji et al., “The role of advanced glycation end products in retinal microvascular leukostasis,” Investigative Ophthalmology and Visual Science, vol. 44, no. 10, pp. 4457–4464, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. C. L. B. Kline, T. L. Schrufer, L. S. Jefferson, and S. R. Kimball, “Glucosamine-induced phosphorylation of the α-subunit of eukaryotic initiation factor 2 is mediated by the protein kinase R-like endoplasmic-reticulum associated kinase,” International Journal of Biochemistry and Cell Biology, vol. 38, no. 5-6, pp. 1004–1014, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Brownlee, “The pathobiology of diabetic complications: a unifying mechanism,” Diabetes, vol. 54, no. 6, pp. 1615–1625, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. R. Marchioli, C. Schweiger, G. Levantesi, L. Tavazzi, and F. Valagussa, “Antioxidant vitamins and prevention of cardiovascular disease: epidemiological and clinical trial data,” Lipids, vol. 36, pp. S53–S63, 2001. View at Scopus
  15. D. W. Dawson, O. V. Volpert, P. Gillis et al., “Pigment epithelium-derived factor: a potent inhibitor of angiogenesis,” Science, vol. 285, no. 5425, pp. 245–248, 1999. View at Publisher · View at Google Scholar · View at Scopus
  16. J. Spranger, M. Osterhoff, M. Reimann et al., “Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease,” Diabetes, vol. 50, no. 12, pp. 2641–2645, 2001. View at Scopus
  17. J. Tombran-Tink and L. V. Johnson, “Neuronal differentiation of retinoblastoma cells induced by medium conditioned by human RPE cells,” Investigative Ophthalmology and Visual Science, vol. 30, no. 8, pp. 1700–1707, 1989. View at Scopus
  18. J. Ortego, J. Escribano, S. P. Becerra, and M. Coca-Prados, “Gene expression of the neurotrophic pigment epithelium-derived factor in the human ciliary epithelium: synthesis and secretion into the aqueous humor,” Investigative Ophthalmology and Visual Science, vol. 37, no. 13, pp. 2759–2767, 1996. View at Scopus
  19. S. P. Becerra, A. Sagasti, P. Spinella, and V. Notario, “Pigment epithelium-derived factor behaves like a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop,” Journal of Biological Chemistry, vol. 270, no. 43, pp. 25992–25999, 1995. View at Publisher · View at Google Scholar · View at Scopus
  20. T. Yabe, D. Wilson, and J. P. Schwartz, “NFκB Activation Is Required for the Neuroprotective Effects of Pigment Epithelium-derived Factor (PEDF) on Cerebellar Granule Neurons,” Journal of Biological Chemistry, vol. 276, no. 46, pp. 43313–43319, 2001. View at Publisher · View at Google Scholar · View at Scopus
  21. H. Liu, J. G. Ren, W. L. Cooper, C. E. Hawkins, M. R. Cowan, and P. Y. Tong, “Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 17, pp. 6605–6610, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. S. X. Zhang, J. J. Wang, G. Gao, C. Shao, R. Mott, and J. X. Ma, “Pigment epithelium-derived factor (PEDF) is an endogenous antiinflammatory factor,” FASEB Journal, vol. 20, no. 2, pp. 323–325, 2006. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Matsuoka, N. Ogata, T. Otsuji, T. Nishimura, K. Takahashi, and M. Matsumura, “Expression of pigment epithelium derived factor and vascular endothelial growth factor in choroidal neovascular neovascular membranes and polypoidal choroidal vasculopathy,” British Journal of Ophthalmology, vol. 88, no. 6, pp. 809–815, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. H. Yang and H. E. Grossniklaus, “Constitutive overexpression of pigment epithelium-derived factor inhibition of ocular melanoma growth and metastasis,” Investigative Ophthalmology & Visual Science, vol. 51, no. 1, pp. 28–34, 2010. View at Scopus
  25. S. I. Yamagishi, Y. Inagaki, S. Amano, T. Okamoto, M. Takeuchi, and Z. Makita, “Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its antioxidative properties,” Biochemical and Biophysical Research Communications, vol. 296, no. 4, pp. 877–882, 2002. View at Publisher · View at Google Scholar · View at Scopus
  26. Y. Yoshida, S. I. Yamagishi, T. Matsui et al., “Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy,” Diabetes/Metabolism Research and Reviews, vol. 25, no. 7, pp. 678–686, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. S. I. Yamagishi, Y. Inagaki, K. Nakamura et al., “Pigment epithelium-derived factor inhibits TNF-α-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation,” Journal of Molecular and Cellular Cardiology, vol. 37, no. 2, pp. 497–506, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. K. Nakamura, S. I. Yamagishi, T. Matsui et al., “Pigment epithelium-derived factor inhibits neointimal hyperplasia after vascular injury by blocking NADPH oxidase-mediated reactive oxygen species generation,” American Journal of Pathology, vol. 170, no. 6, pp. 2159–2170, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. N. Ogata, J. Tombran-Tink, M. Nishikawa et al., “Pigment epithelium-derived factor in the vitreous is low in diabetic retinopathy and high in rhegmatogenous retinal detachment,” American Journal of Ophthalmology, vol. 132, no. 3, pp. 378–382, 2001. View at Publisher · View at Google Scholar · View at Scopus
  30. B. O. Boehm, G. Lang, B. Feldmann et al., “Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. A pilot study,” Hormone and Metabolic Research, vol. 35, no. 6, pp. 382–386, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. B. O. Boehm, G. Lang, O. Volpert et al., “Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy,” Diabetologia, vol. 46, no. 3, pp. 394–400, 2003. View at Scopus
  32. N. Ogata, M. Matsuoka, K. Matsuyama et al., “Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 3, pp. 1176–1179, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. M. P. Cohen, E. Hud, E. Shea, and C. W. Shearman, “Vitreous fluid of db/db mice exhibits alterations in angiogenic and metabolic factors consistent with early diabetic retinopathy,” Ophthalmic Research, vol. 40, no. 1, pp. 5–9, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. L. Notari, A. Miller, A. Martínez et al., “Pigment epithelium-derived factor is a substrate for matrix metalloproteinase type 2 and type 9: implications for downregulation in hypoxia,” Investigative Ophthalmology and Visual Science, vol. 46, no. 8, pp. 2736–2747, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. V. Stellmach, S. E. Crawford, W. Zhou, and N. Bouck, “Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 5, pp. 2593–2597, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. S. I. Yamagishi, T. Matsui, K. Nakamura et al., “Pigment-epithelium-derived factor suppresses expression of receptor for advanced glycation end products in the eye of diabetic rats,” Ophthalmic Research, vol. 39, no. 2, pp. 92–97, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. N. Katakami, H. Kaneto, Y. Yamasaki, and M. Matsuhisa, “Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy,” Diabetes Research and Clinical Practice, vol. 81, no. 1, pp. e4–e7, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. Y. Yoshida, S. I. Yamagishi, T. Matsui et al., “Positive correlation of pigment epithelium-derived factor and total antioxidant capacity in aqueous humour of patients with uveitis and proliferative diabetic retinopathy,” British Journal of Ophthalmology, vol. 91, no. 9, pp. 1133–1134, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. J. J. Wang, S. X. Zhang, R. Mott et al., “Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities,” Diabetes, vol. 55, no. 6, pp. 1678–1685, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. E. J. Duh, H. S. Yang, I. Suzuma et al., “Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth,” Investigative Ophthalmology and Visual Science, vol. 43, no. 3, pp. 821–829, 2002. View at Scopus
  41. S. Gurunathan and E. Duh, “PEDF inhibits VEGF activation of PI3 Kinase/ Akt and Src in human retinal endothelial cells,” Investigative Ophthalmology and Visual Science, vol. 46, 2005.
  42. H. Hutchings, M. Maitre-Boube, J. Tombran-Tink, and J. Plouëta, “Pigment epithelium-derived factor exerts opposite effects on endothelial cells of different phenotypes,” Biochemical and Biophysical Research Communications, vol. 294, no. 4, pp. 764–769, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. H. Mu, X. M. Zhang, J. J. Liu, L. Dong, and Z. L. Feng, “Effect of high glucose concentration on VEGF and PEDF expression in cultured retinal Müller cells,” Molecular Biology Reports, vol. 36, no. 8, pp. 2147–2151, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. S. I. Yamagishi, C. C. Hsu, M. Taniguchi et al., “Receptor-mediated toxicity to pericytes of advanced glycosylation end products: a possible mechanism of pericyte loss in diabetic microangiopathy,” Biochemical and Biophysical Research Communications, vol. 213, no. 2, pp. 681–687, 1995. View at Publisher · View at Google Scholar · View at Scopus
  45. S. I. Yamagishi, S. Amano, Y. Inagaki et al., “Advanced glycation end products-induced apoptosis and overexpression of vascular endothelial growth factor in bovine retinal pericytes,” Biochemical and Biophysical Research Communications, vol. 290, no. 3, pp. 973–978, 2002. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Yamagishi, T. Matsui, and H. Inoue, “Inhibition by advanced glycation end products (AGEs) of pigment epithelium-derived factor (PEDF) gene expression in microvascular endothelial cells,” Drugs under Experimental and Clinical Research, vol. 31, no. 5-6, pp. 227–232, 2005. View at Scopus
  47. L. J. Mandarino, “Current hypotheses for the biochemical basis of diabetic retinopathy,” Diabetes Care, vol. 15, no. 12, pp. 1892–1901, 1992. View at Scopus
  48. R. N. Frank, “On the pathogenesis of diabetic retinopathy: a 1990 update,” Ophthalmology, vol. 98, no. 5, pp. 586–593, 1991. View at Scopus
  49. S. Amano, S. I. Yamagishi, Y. Inagaki et al., “Pigment epithelium-derived factor inhibits oxidative stress-induced apoptosis and dysfunction of cultured retinal pericytes,” Microvascular Research, vol. 69, no. 1-2, pp. 45–55, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. Y. Inagaki, S. Yamagishi, T. Okamoto, M. Takeuchi, and S. Amano, “Pigment epithelium-derived factor prevents advanced glycation end products-induced monocyte chemoattractant protein-1 production in microvascular endothelial cells by suppressing intracellular reactive oxygen species generation,” Diabetologia, vol. 46, no. 2, pp. 284–287, 2003. View at Scopus
  51. Y. Mitamura, S. Takeuchi, A. Matsuda, Y. Tagawa, Y. Mizue, and J. Nishihira, “Monocyte chemotactic protein-1 in the vitreous of patients with proliferative diabetic retinopathy,” Ophthalmologica, vol. 215, no. 6, pp. 415–418, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. A. W. Stitt, “The role of advanced glycation in the pathogenesis of diabetic retinopathy,” Experimental and Molecular Pathology, vol. 75, no. 1, pp. 95–108, 2003. View at Publisher · View at Google Scholar · View at Scopus
  53. S. I. Yamagishi, Y. Inagaki, S. Amano, T. Okamoto, M. Takeuchi, and Z. Makita, “Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its antioxidative properties,” Biochemical and Biophysical Research Communications, vol. 296, no. 4, pp. 877–882, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. T. Okamoto, S. I. Yamagishi, Y. Inagaki et al., “Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin,” The FASEB Journal, vol. 16, no. 14, pp. 1928–1930, 2002. View at Scopus
  55. S. I. Yamagishi, S. Ueda, T. Matsui et al., “Pigment Epithelium-Derived Factor (PEDF) prevents Advanced Glycation End products (AGEs)-elicited endothelial Nitric Oxide Synthase (eNOS) reduction through its anti-oxidative properties,” Protein and Peptide Letters, vol. 14, no. 8, pp. 832–835, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. V. M. Victor and M. Rocha, “Targeting antioxidants to mitochondria: a potential new therapeutic strategy for cardiovascular diseases,” Current Pharmaceutical Design, vol. 13, no. 8, pp. 845–863, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. I. Sudano, L. E. Spieker, F. Hermann et al., “Protection of endothelial function: targets for nutritional and pharmacological interventions,” Journal of Cardiovascular Pharmacology, vol. 47, no. 2, pp. S136–S150, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. S. I. Yamagishi, K. Nakamura, T. Matsui, S. I. Ueda, and T. Imaizumi, “Role of postprandial hyperglycaemia in cardiovascular disease in diabetes,” International Journal of Clinical Practice, vol. 61, no. 1, pp. 83–87, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. K. Takenaka, S. I. Yamagishi, T. Matsui, K. Nakamura, and T. Imaizumi, “Role of advanced glycation end products (AGEs) in thrombogenic abnormalities in diabetes,” Current Neurovascular Research, vol. 3, no. 1, pp. 73–77, 2006. View at Publisher · View at Google Scholar · View at Scopus
  60. S. I. Yamagishi, D. Edelstein, X. L. Du, and M. Brownlee, “Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction,” Diabetes, vol. 50, no. 6, pp. 1491–1494, 2001. View at Scopus
  61. S. I. Yamagishi, T. Matsui, K. Takenaka, K. Nakamura, M. Takeuchi, and H. Inoue, “Pigment epithelium-derived factor (PEDF) prevents platelet activation and aggregation in diabetic rats by blocking deleterious effects of advanced glycation end products (AGEs),” Diabetes/Metabolism Research and Reviews, vol. 25, no. 3, pp. 266–271, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Sheikpranbabu, R. Haribalaganesh, and S. Gurunathan, “Pigment epithelium-derived factor inhibits advanced glycation end-products-induced cytotoxicity in retinal pericytes,” Diabetes and Metabolism, vol. 37, no. 6, pp. 505–511, 2011. View at Publisher · View at Google Scholar
  63. S. Sheikpranbabu, R. Haribalaganesh, E. Banumathi, N. Sirishkumar, K. J. Lee, and S. Gurunathan, “Pigment epithelium-derived factor inhibits advanced glycation end-product-induced angiogenesis and stimulates apoptosis in retinal endothelial cells,” Life Sciences, vol. 85, no. 21-22, pp. 719–731, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. S. I. Yamagishi, S. Amano, Y. Inagaki, T. Okamoto, M. Takeuchi, and H. Inoue, “Pigment epithelium-derived factor inhibits leptin-induced angiogenesis by suppressing vascular endothelial growth factor gene expression through anti-oxidative properties,” Microvascular Research, vol. 65, no. 3, pp. 186–190, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. R. F. Gariano, A. K. Nath, D. J. D'Amico, T. Lee, and M. R. Sierra-Honigmann, “Elevation of vitreous leptin in diabetic retinopathy and retinal detachment,” Investigative Ophthalmology and Visual Science, vol. 41, no. 11, pp. 3576–3581, 2000. View at Scopus
  66. S. I. Yamagishi, Y. Inagaki, K. Nakamura et al., “Pigment epithelium-derived factor inhibits TNF-α-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation,” Journal of Molecular and Cellular Cardiology, vol. 37, no. 2, pp. 497–506, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. W. V. Berghe, L. Vermeulen, G. De Wilde, K. De Bosscher, E. Boone, and G. Haegeman, “Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6,” Biochemical Pharmacology, vol. 60, no. 8, pp. 1185–1195, 2000. View at Publisher · View at Google Scholar · View at Scopus
  68. J. M. Li, A. M. Mullen, S. Yun et al., “Essential role of the NADPH oxidase subunit p47phox in endothelial cell superoxide production in response to phorbol ester and tumor necrosis factor-α,” Circulation Research, vol. 90, no. 2, pp. 143–150, 2002. View at Publisher · View at Google Scholar · View at Scopus
  69. S. I. Yamagishi, K. Nakamura, S. Ueda, S. Kato, and T. Imaizumi, “Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: a novel anti-oxidative mechanism of PEDF,” Cell and Tissue Research, vol. 320, no. 3, pp. 437–445, 2005. View at Publisher · View at Google Scholar · View at Scopus
  70. S. I. Yamagishi, T. Matsui, K. Nakamura, and H. Inoue, “Pigment epithelium-derived factor is a pericyte mitogen secreted by microvascular endothelial cells: possible participation of angiotensin II-elicited PEDF downregulation in diabetic retinopathy,” International Journal of Tissue Reactions, vol. 27, no. 4, pp. 197–202, 2005. View at Scopus
  71. M. Lu and A. P. Adamis, “Vascular endothelial growth factor gene regulation and action in diabetic retinopathy,” Ophthalmology Clinics of North America, vol. 15, no. 1, pp. 69–79, 2002. View at Publisher · View at Google Scholar · View at Scopus
  72. S. X. Zhang, J. J. Wang, A. Dashti et al., “Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein,” Journal of Molecular Endocrinology, vol. 41, no. 3-4, pp. 135–143, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. Z. Zheng, H. Chen, G. Ke et al., “Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor-to-pigment epithelium-derived factor ratio: involvement of a mitochondria-reactive oxygen species pathway,” Diabetes, vol. 58, no. 4, pp. 954–964, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. Z. Zheng, H. Chen, H. Zhao et al., “Inhibition of JAK2/STAT3-mediated VEGF upregulation under high glucose conditions by PEDF through a mitochondrial ROS pathway in vitro,” Investigative Ophthalmology & Visual Science, vol. 51, no. 1, pp. 64–71, 2010. View at Scopus
  75. M. Yokoi, S. I. Yamagishi, A. Saito et al., “Positive association of pigment epithelium-derived factor with total antioxidant capacity in the vitreous fluid of patients with proliferative diabetic retinopathy,” British Journal of Ophthalmology, vol. 91, no. 7, pp. 885–887, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. S. I. Yamagishi, K. Nakamura, T. Matsui et al., “Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression,” Journal of Biological Chemistry, vol. 281, no. 29, pp. 20213–20220, 2006. View at Publisher · View at Google Scholar · View at Scopus
  77. E. Banumathi, S. Sheikpranbabu, R. Haribalaganesh, and S. Gurunathan, “PEDF prevents reactive oxygen species generation and retinal endothelial cell damage at high glucose levels,” Experimental Eye Research, vol. 90, no. 1, pp. 89–96, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. O. A. Anderson, J. W. B. Bainbridge, and D. T. Shima, “Delivery of anti-angiogenic molecular therapies for retinal disease,” Drug Discovery Today, vol. 15, no. 7-8, pp. 272–282, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. R. Longeras, J.-X. Ma, K. Farjo, and M. Ihnat, “A PEDF-derived peptide inhibits retinal neovascularization and blocks mobilization of bone marrow-derived endothelial progenitor cells,” Experimental Diabetes Research, vol. 2012, Article ID 518426, 11 pages, 2012. View at Publisher · View at Google Scholar
  80. R. Herrero-Vanrell and M. F. Refojo, “Biodegradable microspheres for vitreoretinal drug delivery,” Advanced Drug Delivery Reviews, vol. 52, no. 1, pp. 5–16, 2001. View at Publisher · View at Google Scholar · View at Scopus
  81. M. K. Yeh, S. M. Tung, D. W. Lu, J. L. Chen, and C. H. Chiang, “Formulation factors for preparing ocular biodegradable delivery system of 5-fluorouracil microparticles,” Journal of Microencapsulation, vol. 18, no. 4, pp. 507–519, 2001. View at Publisher · View at Google Scholar · View at Scopus
  82. H. Li, V. V. Tran, Y. Hu, W. Mark Saltzman, C. J. Barnstable, and J. Tombran-Tink, “A PEDF N-terminal peptide protects the retina from ischemic injury when delivered in PLGA nanospheres,” Experimental Eye Research, vol. 83, no. 4, pp. 824–833, 2006. View at Publisher · View at Google Scholar · View at Scopus
  83. G. G. Giordano, P. Chevez-Barrios, M. F. Refojo, and C. A. Garcia, “Biodegradation and tissue reaction to intravitreous biodegradable poly(D,L-lactic-co-glycolic)acid microspheres,” Current Eye Research, vol. 14, no. 9, pp. 761–768, 1995. View at Scopus
  84. P. A. Campochiaro, Q. D. Nguyen, S. M. Shah et al., “Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial,” Human Gene Therapy, vol. 17, no. 2, pp. 167–176, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. K. Park, J. Jin, Y. Hu, K. Zhou, and J.-X. Ma, “Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization,” American Journal of Pathology, vol. 178, no. 2, pp. 688–698, 2011. View at Publisher · View at Google Scholar