Role of extracellular signal-regulated kinase for endothelial progenitor cell dysfunction in coronary artery disease
Role of extracellular signal-regulated kinase for endothelial progenitor cell dysfunction in coronary artery disease
复制标题
DOI：
10.1007/s00395-009-0022-6
复制
发表时间：
2009-09-01
影响因子：
9.5
通讯作者：
Scheller, Bruno
中科院分区：
文献类型：
--
作者：
Friedrich, Erik B.;Werner, Christian;Scheller, Bruno
冠状动脉疾病（CAD）患者内皮祖细胞（EPCs）的数量和功能下调。与CAD中EPCs功能障碍相关的细胞内信号传导机制仍然缺乏特征。我们的目的是研究SDF-1对ERK-1/2的调控以及ERK-1/2在EPCs粘附中的作用。Western分析显示，在健康对照的EPCs中，趋化因子SDF-1 （SDF-1, 100 nM）在90 s后介导ERK-2的磷酸化，在180-300 s后达到最大值，而CAD患者的EPCs的特点是SDF-1触发的ERK-2磷酸化在时间上延迟，在数量上显著减弱。在功能上，从CAD患者分离的EPCs在流动条件下显示出sdf -1诱导的粘附减少，而通过激活MEK-2 cDNA构建增强ERK-2信号，将粘附恢复到控制水平，并挽救CAD-EPCs的粘附缺陷。这些数据表明，sdf -1引发的EPC粘附缺陷导致了CAD中EPCs的功能损伤，而ERK-2代表了CAD中EPC粘附功能改善的新治疗靶点。
In patients with coronary artery disease (CAD), number and function of endothelial progenitor cells (EPCs) are down-regulated. The relevant intracellular signalling mechanisms responsible for dysfunction of EPCs in CAD remain poorly characterized. Our goal was to examine the regulation of ERK-1/2 by SDF-1 and the role of ERK-1/2 for adhesion in EPCs. Western analysis revealed that the chemokine SDF-1 (SDF-1, 100 nM) mediates phosphorylation of ERK-2 after 90 s with a maximum after 180-300 s in EPCs isolated from healthy control subjects, while EPCs from patients with CAD are characterized by a temporally delayed and quantitatively markedly attenuated SDF-1-triggered ERK-2-phosphorylation. Functionally, EPCs isolated from patients with CAD display reduced SDF-1-induced adhesion under flow conditions, while augmenting ERK-2 signalling using an activating MEK-2 cDNA construct restores adhesion to control levels and rescues the adhesion defect of CAD-EPCs. These data indicate that defects in SDF-1-triggered EPC-adhesion contribute to the functional impairment of EPCs in CAD, and that ERK-2 represents a new therapeutic target for functional improvement of EPC adhesion in CAD.