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G.-T. Xu, J. Shen, Y. Wu, J.-Y. Xu, J. Zhang, S. H. Sinclair, G. Xu, M. Yanoff, W. Li; Apoptosis-Inducing Property of Anti-VEGF Treatments in Retinal Neuronal Cells via Regulation of BH3-Only Protein Bim. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5986.
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© ARVO (1962-2015); The Authors (2016-present)
Anti-VEGF therapy has increasingly gained its popularity in treating retinal diseases with neovascularization. However, safety concerns about the continual blockade of VEGF are emerging. The goal of this study is to explore the underlying molecular mechanisms of the toxicity induced by anti-VEGF treatments, and to find out possible solutions to solve this problem.
Primary rat retinal neuron culture and R28 (an immortalized rat retinal neuron cell line) were used in the present study. After treatments with anti-VEGF drugs with or without EPO, the retinal cells were evaluated by TUNEL staining, mitochondrial membrane potential detection (JC-1 staining) and substantiated by electron microscopy (EM). Western blots and real-time RT PCR indicated the expressions of Bim under these treatments were regulated at both protein and mRNA levels, which were confirmed by ubiquitination assay and Luciferase activity assay.
Anti-VEGF treatments caused significant increase of apoptosis in both primary retinal neurons and in R28 as indicated by TUNEL staining, changes of mitochondrial membrane potential and electron transmission microscopy. It was shown that the BH3-only protein Bim, a proapoptotic member of Bcl-2 family, played an essential role in the toxicity induced by anti-VEGF treatments. The regulation of Bim during apoptosis induction stemmed from the transcriptional and post-translational regulatory mechanisms. Interestingly, the neuroprotectant erythropoietin (EPO) showed beneficial effects upon anti-VEGF treatment induced apoptosis.
The apoptosis-inducing functions of anti-VEGF treatments in retinal neurons were demonstrated, which could be alleviated by exogenous EPO. The present data also indicate that the proapoptotic BH3-only protein Bim played pivotal roles in these processes.
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