Ruboxistaurin, a PKCbeta inhibitor, inhibits retinal neovascularization via suppression of phosphorylation of ERK1/2 and Akt.
Ruboxistaurin, a protein kinase C (PKC) beta inhibitor, exhibits significant anti-angiogenic activity that reduces the response of vascular endothelial cells to stimulation by vascular endothelial growth factor (VEGF). In addition, the activation of PKC, specifically PKCbeta, plays a key role in the retinal neovascularization. However, the effect of ruboxistaurin on oxygen-induced retinopathy (OIR), an experimental murine model of proliferative retinopathy, has not yet been investigated. In this study, we assessed the efficacy of ruboxistaurin both in vitro and in vivo and also evaluated its anti-angiogenic mechanisms. Ruboxistaurin inhibited formation, proliferation, and migration of VEGF-induced human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. It also inhibited the VEGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and serine/threonine protein kinase family protein kinase B (Akt). In in vivo retinal neovascularization experiments, induced in neonatal mice by returning the retina to normoxia (21% O2) after exposure to hyperoxia (75% O2), ruboxistaurin given subcutaneously significantly reduced pathologic vascular changes. No effect was seen on revascularization of the capillary-free area. These findings indicate that ruboxistaurin has anti-angiogenic effects both in vitro and in vivo that are exerted partly via suppressing the phosphorylation of ERK1/2 and Akt. Ruboxistaurin may be a candidate for treatment of angiogenesis in retinal neovascularization diseases.
Nakamura
Shinsuke
S
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Chikaraishi
Yuichi
Y
Tsuruma
Kazuhiro
K
Shimazawa
Masamitsu
M
Hara
Hideaki
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000378:metabolism / Q000517:prevention & control*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D042461:Vascular Endothelial Growth Factor A; C099154:ruboxistaurin; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3