Bactericidal/permeability-increasing protein's signaling pathways and its retinal trophic and anti-angiogenic effects.
Bactericidal/permeability-increasing protein (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
Michiko
M
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Rook
Susan L
SL
Sassa
Yukio
Y
Ma
Ronald C
RC
Geraldes
Pedro
P
Goddard
Lucy
L
Clermont
Allen
A
Gao
Benbo
B
Salti
Haytham
H
Gundel
Robert
R
White
Mark
M
Feener
Edward P
EP
Aiello
Lloyd Paul
LP
King
George L
GL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000032:analysis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001798:Blood Proteins / Q000032:analysis / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010949:Plasma / Q000737:chemistry; D011994:Recombinant Proteins / Q000494:pharmacology; D012160:Retina / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects* / Q000254:growth & development; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014822:Vitreous Body / Q000737:chemistry
D020533:Angiogenesis Inhibitors; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C021623:bactericidal permeability increasing protein