Role of inflammation and insulin resistance in endothelial progenitor cell dysfunction.
Role of inflammation and insulin resistance in endothelial progenitor cell dysfunction.
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DOI：
10.2337/db10-0875
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发表时间：
2011-04
期刊：
影响因子：
7.7
通讯作者：
O'Connell K
中科院分区：
文献类型：
--
作者：
Desouza CV;Hamel FG;Bidasee K;O'Connell K
2型糖尿病患者的内皮祖细胞（EPCs）数量和功能减少。这种功能障碍发生的机制在很大程度上是未知的。我们检验了慢性炎症环境导致EPCs胰岛素信号传导缺陷从而降低其存活率的假设。通过敲低核因子-κB（NF-κB）修饰EPCs可以逆转胰岛素信号转导缺陷，提高EPCs存活率，减少血管成形术后新生内膜增生。培养Zucker脂肪胰岛素抵抗大鼠的EPCs，并将其暴露于肿瘤坏死因子-α（TNF-α）中。在存在和不存在NF-κB抑制剂BAY 11的情况下测量胰岛素信号传导缺陷和细胞凋亡。然后，通过敲低NF-κB（RelA）修饰EPCs并暴露于TNF-α。对于体内实验，Zucker肥胖大鼠在颈动脉血管成形术后给予修饰的EPCs。在不同时间点追踪内皮祖细胞，3周后测量新生内膜增生。在暴露于TNF-α的EPCs中，通过磷酸化AKT与总AKT的比率测量的胰岛素信号传导降低了56%。细胞凋亡增加71%。用NF-κB抑制剂BAY 11预处理可逆转这些缺陷。暴露于TNF-α的修饰EPCs显示胰岛素刺激的AKT磷酸化减少较少（RelA 20%），而未修饰EPCs减少55%。RelA基因敲低的EPCs细胞凋亡减少41%。接受改良EPCs的大鼠血管成形术后新生内膜增生明显少于对照组（内膜-中膜比0.58 vs.1.62）。总之，我们已经表明，胰岛素信号转导和EPC生存受损Zucker脂肪胰岛素抵抗大鼠。这是我们第一次发现NF-κB的敲低可以显著改善这种缺陷，并且给予Zucker肥胖大鼠这些EPCs可以减少颈动脉血管成形术后的新生内膜增生。
Endothelial progenitor cells (EPCs) are decreased in number and function in type 2 diabetes. Mechanisms by which this dysfunction occurs are largely unknown. We tested the hypothesis that a chronic inflammatory environment leads to insulin signaling defects in EPCs and thereby reduces their survival. Modifying EPCs by a knockdown of nuclear factor-κB (NF-κB) can reverse the insulin signaling defects, improve EPC survival, and decrease neointimal hyperplasia in Zucker fatty rats postangioplasty. EPCs from Zucker fatty insulin-resistant rats were cultured and exposed to tumor necrosis factor-α (TNF-α). Insulin signaling defects and apoptosis were measured in the presence and absence of an NF-κB inhibitor, BAY11. Then, EPCs were modified by a knockdown of NF-κB (RelA) and exposed to TNF-α. For in vivo experiments, Zucker fatty rats were given modified EPCs post–carotid angioplasty. Tracking of EPCs was done at various time points, and neointimal hyperplasia was measured 3 weeks later. Insulin signaling as measured by the phosphorylated–to–total AKT ratio was reduced by 56% in EPCs exposed to TNF-α. Apoptosis was increased by 71%. These defects were reversed by pretreatment with an NF-κB inhibitor, BAY11. Modified EPCs exposed to TNF-α showed a lesser reduction (RelA 20%) in insulin-stimulated AKT phosphorylation versus a 55% reduction in unmodified EPCs. Apoptosis was 41% decreased for RelA knockdown EPCs. Noeintimal hyperplasia postangioplasty was significantly less in rats receiving modified EPCs than in controls (intima-to-media ratio 0.58 vs. 1.62). In conclusion, we have shown that insulin signaling and EPC survival is impaired in Zucker fatty insulin resistant rats. For the first time, we have shown that this defect can be significantly ameliorated by a knockdown of NF-κB and that these EPCs given to Zucker fatty rats decrease neointimal hyperplasia post–carotid angioplasty.
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影响因子：
2.7
作者：
Kast, RE
通讯作者：
Kast, RE
影响因子：
15.9
作者：
Gallagher, Katherine A.;Liu, Zhao-Jun;Velazquez, Omaida C.
通讯作者：
Velazquez, Omaida C.
影响因子：
6
作者：
Bellezza, Ilaria;Neuwirt, Hannes;Culig, Zoran
通讯作者：
Culig, Zoran
影响因子：
4.8
作者：
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通讯作者：
Liu, Zhenqi
DOI：
10.1016/j.bbrc.2005.01.140
发表时间：
2005-04-01
影响因子：
3.1
作者：
Csehi, SB;Mathieu, S;Adam, D
通讯作者：
Adam, D