Murdoch Colin E, Bachschmid Markus M, Matsui Reiko
*Vascular Medicine Section, Aston Medical School Aston University, Aston Triangle, Birmingham B47 ET, U.K.
†Vascular Biology Section, Boston University Medical School, Boston, MA 02118, U.S.A.
Biochem Soc Trans. 2014 Dec;42(6):1665-70. doi: 10.1042/BST20140213.
S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflammation by regulating the activity of nuclear factor κB (NF-κB) and actin polymerization. Vascular endothelial growth factor (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 hindlimb ischaemia (HLI). Wnt5a and soluble Fms-like tyrosine kinase-1 (sFlt-1) were enhanced in the ischaemic-limb muscle and plasma respectively from Glrx transgenic (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 the Wnt5a/sFlt-1 pathway through enhancing NF-κB signalling. These studies show a novel role for Glrx in post-ischaemic neovascularization, which could define a potential target for therapy of impaired angiogenesis in pathological conditions including diabetes.
当活性氧或氮物质与蛋白质半胱氨酸硫醇发生反应时，就会发生S-谷胱甘肽化。谷氧还蛋白-1（Glrx）是一种胞质酶，可酶促催化S-谷胱甘肽化的还原，赋予具有氧化还原敏感性硫醇的蛋白质可逆的信号传导功能。Glrx可通过调节核因子κB（NF-κB）的活性和肌动蛋白聚合来调节血管肥大和炎症。Glrx过表达会抑制血管内皮生长因子（VEGF）诱导的内皮细胞（EC）迁移。在过表达Glrx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。在Glrx转基因（TG）小鼠的缺血肢体肌肉和血浆中，Wnt5a和可溶性Fms样酪氨酸激酶-1（sFlt-1）分别增强。在控制视网膜血管发育的髓样细胞中已描述了一条Wnt5a/sFlt-1信号通路。有趣的是，还发现一条Wnt5a/sFlt-1信号通路在EC中发挥作用以抑制网络形成。NF-κB组分的S-谷胱甘肽化会抑制其激活。上调的Glrx通过增强NF-κB信号传导刺激Wnt5a/sFlt-1信号通路。这些研究表明Glrx在缺血后新生血管形成中具有新作用，这可能为包括糖尿病在内的病理状况下血管生成受损的治疗确定一个潜在靶点。
