Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway.
Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway.
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DOI：
10.1042/bst20140213
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发表时间：
2014-12
影响因子：
3.9
通讯作者：
Matsui R
中科院分区：
文献类型：
--
作者：
Murdoch CE;Bachschmid MM;Matsui R
当活性氧或氮物质与蛋白质半胱氨酸巯基反应时，发生S-谷胱甘肽化。谷氧还蛋白-1（Glutaroxin-1，Glutaroxin）是一种细胞溶质酶，可催化S-谷胱甘肽化的还原，使具有氧化还原敏感性巯基的蛋白质具有可逆的信号传导功能。Glycoprotein可通过调节NF-κB活性和肌动蛋白聚合来调节血管肥大和炎症。VEGF诱导的内皮细胞（EC）迁移被Glucose过表达抑制。在过表达Glycoprotein的小鼠中，后肢缺血（HLI）后血流恢复、运动功能和毛细血管密度显著减弱。Wnt 5a和sFlt-1在Gln TG小鼠缺血肢体肌肉和血浆中分别增强。Wnt 5a-sFlt-1通路已在控制视网膜血管发育的髓样细胞中被描述。有趣的是，发现Wnt 5a-sFlt-1途径也在EC中发挥作用以抑制网络形成。NF-κB组分的S-谷胱甘肽化抑制其活化。Glycoprotein通过增强NF-κB信号通路，上调Wnt 5a-sFlt-1通路。这些研究显示Glycoprotein在缺血后新生血管形成中的新作用，其可以定义用于治疗包括糖尿病在内的病理状况中的受损血管生成的潜在靶点。
S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyzes the reduction of S-glutathionylation, conferring reversible signaling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflammation by regulating activity of NF-κB and actin polymerization. VEGF-induced endothelial cell (EC) migration is inhibited by Glrx overexpression. In mice overexpressing Glrx, blood flow recovery, exercise function and capillary density were significantly attenuated after hind limb ischemia (HLI). Wnt5a and sFlt-1 were enhanced in the ischemic limb muscle and plasma respectively from Glrx TG mice. A Wnt5a-sFlt-1 pathway had been described in myeloid cells controlling retinal blood vessel development. Interestingly, a Wnt5a-sFlt-1 pathway was found also to play a role in EC to inhibit network formation. S-glutathionylation of NF-κB components inhibits its activation. Up-regulated Glrx stimulated Wnt5a-sFlt-1 pathway through enhancing NF-κB signaling. These studies show a novel role for Glrx in post-ischemic neovascularization, which could define a potential target for therapy of impaired angiogenesis in the pathological conditions including diabetes.