Glutaredoxin-1 Up-regulation Induces Soluble Vascular Endothelial Growth Factor Receptor 1, Attenuating Post-ischemia Limb Revascularization
Glutaredoxin-1 Up-regulation Induces Soluble Vascular Endothelial Growth Factor Receptor 1, Attenuating Post-ischemia Limb Revascularization
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DOI：
10.1074/jbc.m113.517219
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发表时间：
2014-03-21
影响因子：
4.8
通讯作者：
Matsui, Reiko
中科院分区：
文献类型：
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作者：
Murdoch, Colin E.;Shuler, Michaela;Matsui, Reiko
背景：谷氧还蛋白-1（Glutaredoxin-1，Glutarin）通过逆转蛋白-谷胱甘肽加合物抑制内皮细胞迁移。结果：Glycoprotein转基因小鼠后肢缺血后血管重建受到抑制。Glrx过表达通过NF-B依赖性Wnt 5a的产生增加内皮细胞中可溶性VEGF受体1（sFlt）。结论：Glycoprotein增强Wnt 5a诱导的内皮细胞抗血管生成sFlt。重要性：Glutaredoxin-1（Glutaredoxin-1，Glutaredoxin-1）是一种胞浆酶，通过从包括信号分子和转录因子在内的S-谷胱甘肽化蛋白中去除GSH加合物来调节多种细胞功能。在炎症和糖尿病期间，Glycoprotein上调，Glycoprotein过表达抑制VEGF诱导的EC迁移。目的是研究在后肢缺血的情况下，上调的Glycoprotein在EC血管生成能力和体内血运重建中的作用。Glrx过表达的转基因小鼠EC迁移和网络形成受损，并分泌更高水平的可溶性VEGF受体1（sFlt），VEGF的拮抗因子。在后肢缺血手术后，与野生型同窝小鼠相比，Glucose TG小鼠表现出血流恢复受损，与较低的毛细血管密度和较差的肢体运动功能相关。在手术后GlaNTG小鼠的肌肉和血浆中也存在较高水平的抗血管生成sFlt表达。已知非典型Wnt 5a诱导sFlt。Wnt 5a在Glycogen TG小鼠的缺血肌肉和EC中高度表达，外源性Wnt 5a诱导人微血管EC中sFlt的表达并抑制其网络形成。腺病毒Glrx诱导的sFlt在EC中被竞争性Wnt 5a抑制剂抑制。此外，Glycoprotein过表达去除了缺血肌肉和EC中p65上的GSH加合物，并增强了NF-B活性，这是Wnt 5a-sFlt诱导的原因。总之，上调的Glycoprotein通过NF-B依赖性Wnt 5a诱导EC中的sFlt，导致后肢缺血中的血管再生减弱。Glrx诱导的sFlt解释了氧化还原调节VEGF信号传导的部分机制。
Background: Glutaredoxin-1 (Glrx) inhibits endothelial cell migration by reversing protein-glutathione adducts. Results: Revascularization after hind limb ischemia was inhibited in Glrx transgenic mice. Glrx overexpression increased soluble VEGF receptor 1 (sFlt) in endothelial cells via NF-B-dependent Wnt5a production. Conclusion: Glrx enhances Wnt5a-induced anti-angiogenic sFlt in endothelial cells. Significance: Up-regulated Glrx inhibits VEGF signaling by increased sFlt causing impaired vascularization.Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes, and Glrx overexpression inhibits VEGF-induced EC migration. The aim was to investigate the role of up-regulated Glrx in EC angiogenic capacities and in vivo revascularization in the setting of hind limb ischemia. Glrx-overexpressing EC from Glrx transgenic (TG) mice showed impaired migration and network formation and secreted higher levels of soluble VEGF receptor 1 (sFlt), an antagonizing factor to VEGF. After hind limb ischemia surgery Glrx TG mice demonstrated impaired blood flow recovery, associated with lower capillary density and poorer limb motor function compared with wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Noncanonical Wnt5a is known to induce sFlt. Wnt5a was highly expressed in ischemic muscles and EC from Glrx TG mice, and exogenous Wnt5a induced sFlt expression and inhibited network formation in human microvascular EC. Adenoviral Glrx-induced sFlt in EC was inhibited by a competitive Wnt5a inhibitor. Furthermore, Glrx overexpression removed GSH adducts on p65 in ischemic muscle and EC and enhanced NF-B activity, which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-B-dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt explains part of the mechanism of redox-regulated VEGF signaling.