Ruboxistaurin, a PKCβ inhibitor, inhibits retinal neovascularization via suppression of phosphorylation of ERK1/2 and Akt

Ruboxistaurin, a protein kinase C (PKC) β 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 PKCβ, 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 neovasuclarization 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.