Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia.
Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia.
复制标题
在糖尿病肢体缺血中，提高 CXCR7 通过 Akt/GSK-3 beta/Fyn 介导的 Nrf2 激活改善 EPC 的血管生成功能
DOI：
10.1161/circresaha.117.310619
复制
发表时间：
2017-03-03
影响因子：
20.1
通讯作者：
Tan Y
中科院分区：
文献类型：
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作者：
Dai X;Yan X;Zeng J;Chen J;Wang Y;Chen J;Li Y;Barati MT;Wintergerst KA;Pan K;Nystoriak MA;Conklin DJ;Rokosh G;Epstein PN;Li X;Tan Y
内皮祖细胞（EPCs）通过受体CXCR7和CXCR4响应SDF-1。SDF-1受体是否参与糖尿病诱导的EPCs功能障碍尚不清楚。探讨SDF-1受体在糖尿病EPCs功能障碍中的作用。在db/db小鼠的EPCs中，CXCR7表达降低，而CXCR4表达不降低，这与管形成受损相一致。CXCR7的下调会损害正常小鼠EPCs的管状形成，而CXCR7的上调可恢复db/db小鼠EPCs的血管生成功能。在正常的EPCs中，氧化低密度脂蛋白（ox-LDL）或高糖（HG）处理也降低了CXCR7的表达，破坏了小管的形成，增加了氧化应激和细胞凋亡。SDF-1预处理在CXCR7慢病毒转导的EPCs （CXCR7-EPCs）中显著降低ox-LDL或HG的损伤作用，而在对照慢病毒转导的EPCs （Null-EPCs）中则没有。最重要的是，CXCR7-EPCs在治疗db/db小鼠缺血肢体方面优于Null-EPCs。机制研究表明，ox-LDL或HG抑制Akt和GSK-3β磷酸化、Fyn核输出和Nrf2核定位，钝化Nrf2下游靶基因HO-1、NQO-1和过氧化氢酶，诱导EPC氧化应激增加。在CXCR7-EPCs中，SDF-1处理可阻断这种破坏性级联反应。此外，抑制PI3K/Akt可阻止SDF-1/ cxcr7介导的Nrf2激活并阻断血管生成修复。此外，Nrf2敲除几乎完全消除了SDF-1/CXCR7对EPC功能的保护作用。CXCR7表达升高可增强EPCs对糖尿病性肢体缺血的抵抗，提高EPCs对糖尿病性肢体缺血的治疗效果。CXCR7的益处主要通过Akt/GSK-3β/Fyn通路通过Nrf2活性增加介导。
Endothelial progenitor cells (EPCs) respond to SDF-1 through receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes induced EPCs dysfunction remains unknown. To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. CXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, while up-regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein (ox-LDL) or high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox-LDL or HG were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus (CXCR7-EPCs) but not in EPCs transduced with control lentivirus (Null-EPCs). Most importantly, CXCR7-EPCs were superior to Null-EPCs for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that ox-LDL or HG inhibited Akt and GSK-3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, blunting Nrf2 downstream target genes HO-1, NQO-1 and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in CXCR7-EPCs. Furthermore, inhibition of PI3K/Akt prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo. Elevated expression of CXCR7 enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by an Akt/GSK-3β/Fyn pathway via increased activity of Nrf2.