Inhibition of reactive gliosis prevents neovascular growth in the mouse model of oxygen-induced retinopathy.
Inhibition of reactive gliosis prevents neovascular growth in the mouse model of oxygen-induced retinopathy.
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DOI：
10.1371/journal.pone.0022244
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Al-Mohanna FA
中科院分区：
文献类型：
--
作者：
DeNiro M;Al-Mohanna FH;Al-Mohanna FA
视网膜新生血管（NV）是缺血性视网膜病失明的主要原因。先前的研究表明，缺血会上调 GFAP 和 PDGF-B 的表达。 GFAP 过度表达是反应性神经胶质增生（RG）的标志，这是视网膜损伤的主要病理生理学特征。此外，PDGF-B 与增殖性视网膜病有关。本研究的目的是深入了解调节 PDGF-B 和 GFAP 表达的可能药物干预措施及其对 RG 和 NV 的影响。我们使用一系列测定法来评估 YC-1（一种 HIF-1 的小分子抑制剂和一种新型的不依赖于 NO 的可溶性鸟苷酸环化酶 (sGC) 激活剂）对 RG 和 NV 的体内和体外影响。与 DMSO 处理的视网膜相比，在体内双重玻璃体内注射 YC-1：（1）抑制了氧诱导视网膜病变（OIR）小鼠模型视网膜中新生血管芽的发育和伸长； (2) 分别降低了缺血诱导的 GFAP 和 PDGF-B 在信息中的过度表达（分别降低了 64.14±0.5% 和 70.27±0.04%）和蛋白质水平（降低了 65.52±0.02% 和 57.59±0.01%）。此外，在 100 µM 浓度下，YC-1 治疗分别下调了 rMC-1 细胞（71.42±0.02% 和 75±0.03%）和 R28 细胞（58.62±0.02% 和 50.00±0.02%）中缺氧诱导的 GFAP 和 PDGF-B 过度表达。而rMC-1细胞中的GFAP和PDGF-B的蛋白水平分别降低了78.57±0.02%和77.55±0.01%，R28细胞中的GFAP和PDGF-B的蛋白水平分别降低了81.44±0.02%和79.16±0.01%。我们证明 YC-1 通过损害神经胶质细胞中 GFAP 和 PDGF-B 的表达来逆转缺血性视网膜病变期间的 RG。这是第一个深入探讨缺血性视网膜血管病变期间 RG 逆转的研究。此外，研究表明YC-1可能在视网膜和神经元病理的治疗中发挥有希望的治疗作用。
Retinal neovascularization (NV) is a major cause of blindness in ischemic retinopathies. Previous investigations have indicated that ischemia upregulates GFAP and PDGF-B expression. GFAP overexpression is a hallmark of reactive gliosis (RG), which is the major pathophysiological feature of retinal damage. In addition, PDGF-B has been implicated in proliferative retinopathies. It was the aim of this study to gain insights on the possible pharmacological interventions to modulate PDGF-B and GFAP expression, and its influence on RG and NV. We used an array of assays to evaluate the effects of YC-1, a small molecule inhibitor of HIF-1 and a novel NO-independent activator of soluble guanylyl cyclase (sGC), on RG and NV, in vivo and in vitro. When compared to the DMSO-treated retinas, dual-intravitreal injections of YC-1, in vivo: (1) suppressed the development and elongation of neovascular sprouts in the retinas of the oxygen-induced retinopathy (OIR) mouse model; and (2) reduced ischemia-induced overexpression of GFAP and PDGF-B at the message (by 64.14±0.5% and 70.27±0.04%) and the protein levels (by 65.52±0.02% and 57.59±0.01%), respectively. In addition, at 100 µM, YC-1 treatment downregulated the hypoxia-induced overexpression of GFAP and PDGF-B at the message level in rMC-1 cells (by 71.42±0.02% and 75±0.03%), and R28 cells (by 58.62±0.02% and 50.00±0.02%), respectively; whereas, the protein levels of GFAP and PDGF-B were reduced (by 78.57±0.02% and 77.55±0.01%) in rMC-1cells, and (by 81.44±0.02% and 79.16±0.01%) in R28 cells, respectively. We demonstrate that YC-1 reversed RG during ischemic retinopathy via impairing the expression of GFAP and PDGF-B in glial cells. This is the first investigation that delves into the reversal of RG during ischemic retinal vasculopathies. In addition, the study reveals that YC-1 may exert promising therapeutic effects in the treatment of retinal and neuronal pathologies.
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影响因子：
4.4
作者：
Dismuke, William M.;Sharif, Najam A.;Ellis, Dorette Z.
通讯作者：
Ellis, Dorette Z.
影响因子：
2.6
作者：
Brioni, JD;Nakane, M;Sullivan, JP
通讯作者：
Sullivan, JP
影响因子：
3.6
作者：
Friebe, A;Koesling, D
通讯作者：
Koesling, D
影响因子：
4.1
作者：
CUNHAVAZ, J;FARIADEABREU, JR;FIGO, GM
通讯作者：
FIGO, GM
影响因子：
7.3
作者：
Kaur, C.;Sivakumar, V.;Ling, E. A.
通讯作者：
Ling, E. A.