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Jiawen Fan, Gezhi Xu; Heme Oxygenase-1 Mediates Nrf2-dependent Protection of Neurons and Vascular Endothelial Cells in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4446.
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Heme oxygenase-1(HO-1) is a novel enzyme with potent anti-inflammatory, anti-oxidant and anti-proliferative effects. The expression of HO-1 via Nrf2/ERK pathway has been shown to play a key role in some oncoma and hematologic diseases. This research aims to investigate the protective effects of HO-1 in streptozotocin(STZ)-induced diabetic rats’ retina and explore the potential mechanism.
We identified Heme/ZnPP-IX as inducer/inhibitor of heme oxygenase-1(HO-1) in müller cells which were isolated from Sprague-Dawley (SD) rats’ eyes and cultured in vitro.100 SD rats were induced to diabetes by STZ injection and monitored at several time points (2 week, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks) for HO-1, HIF-1α,VEGF,SOD-1,P53 and bcl-2 protein and mRNA expression using immunohistochemical and biochemical methods. The expression of HO-1,Nrf-2 and ERK were confirmed by real-time PCR, Western immunoblot analysis and immunohistochemistry in müller cells cultured by DMEM contained high and normal concentrations of glucose. Human vascular endothelial cells were co-cultured with müller cells pretreated by heme and ZnPP-IX and the expression of VEGF were detected.
Heme/ZnPP-IX significantly increased/blocked HO-1 expression combined with accordant changes of Nrf2/ERK gene expression and further down-regulated/up-regulated the expression of VEGF in vascular endothelial cells. Retinal ganglion cells and photoreceptors displayed greater sensitivity to apoptosis when HO-1 expression was inhibited. Concurrently, overexpression of HO-1 was associated with an increase in the activation of HIF-1α, SOD-1,bcl-2 and a decrease in the expression of p53 and VEGF.
HO-1 is an important positive modulator of Nrf2/ARE-dependent signaling that counteracts diabetic-retinopathy-mediated injuries in retinal neurons and vascular endothelial cells. The anti-inflammatory, anti-apoptosis and anti-proliferative mechanisms of HO-1 may be related to the induction of HIF-1α, SOD-1 and bcl-2 and to the suppression of p53,VEGF.
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