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Bactericidal/permeability-increasing protein’s signaling pathways and its retinal trophic and anti-angiogenic effects

Michiko Yamagata^*, Susan L. Rook^*, Yukio Sassa^*, Ronald C. Ma^*, Pedro Geraldes^*, Lucy Goddard^*, Allen Clermont^*,, Benbo Gao^*, Haytham Salti^*,, Robert Gundel, Mark White, Edward P. Feener^*,||, Lloyd Paul Aiello^*,,¶ and George L. King^*,||,1

^* Research Division and

Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA;

Departments of Preclinical Research and Cellular and

Analytical Development, XOMA (US) LLC, Berkeley, California, USA; and Departments of

^|| Medicine and

^¶ Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA

¹Correspondence: Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215, USA. E-mail: george.king{at}joslin.harvard.edu

Bactericidal/permeability-increasingprotein (BPI) was originally identified as a lipopolysaccharide (LPS) binding protein with Gram-negative bactericidal activity in the leukocytes. In this study, we characterized the previously unknown effects of BPI in the eye and the molecular mechanisms involved in its action. BPI mRNA was detected in bovine retina; retinal pigment epithelium; and primary cultures of bovine retinal pigment epithelial cells (RPE), pericytes (RPC), and endothelial cells (REC); while BPI protein was measured in human vitreous and plasma. BPI, but not control protein thaumatin, activated extracellular regulated kinase (ERK) and AKT, and increased DNA synthesis in RPE and RPC but not in REC. A human recombinant 21 kDa modified amino-terminal fragment of BPI (rBPI₂₁) reduced H₂O₂-induced apoptosis in RPE and inhibited vascular endothelial growth factor (VEGF)-stimulated ERK phosphorylation in REC when preincubated with VEGF. Intraperitoneal (i.p.)-injected rBPI21 reduced ischemia-induced retinal neovascularization and diabetes-induced retinal permeability. Since BPI has unusual dual properties of promoting RPC and RPE growth while suppressing VEGF-induced REC growth and vascular permeability, the mechanistic understanding of BPI’s action may provide novel therapeutic opportunities for diabetic retinopathy and age-related macular degeneration.—Yamagata, M., Rook, S. L., Sassa, Y., Ma, R. C., Geraldes, P., Goddard, L., Clermont, A., Gao, B., Salti, H., Gundel, R., White, M., Feener, E. P., Aiello, L. P., and King, G. L. Bactericidal/permeability-increasing protein’s signaling pathways and its retinal trophic and anti-angiogenic effects.

Key Words: ERK • Akt • diabetic retinopathy • age-related macular degeneration • glypican 4

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				A. Abedin, I. Mohammed, A. Hopkinson, and H. S. Dua A Novel Antimicrobial Peptide on the Ocular Surface Shows Decreased Expression in Inflammation and Infection Invest. Ophthalmol. Vis. Sci., January 1, 2008; 49(1): 28 - 33. [Abstract] [Full Text] [PDF]

				P. Geraldes, M. Yamagata, S. L. Rook, Y. Sassa, R. C. Ma, A. Clermont, B. Gao, L. P. Aiello, E. P. Feener, and G. L. King Glypican 4, a Membrane Binding Protein for Bactericidal/Permeability-Increasing Protein Signaling Pathways in Retinal Pigment Epithelial Cells Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5750 - 5755. [Abstract] [Full Text] [PDF]