Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species.
Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species.
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裂解的高分子量激肽原通过诱导活性氧加速内皮祖细胞衰老的发生
DOI：
10.1161/atvbaha.110.222430
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Colman RW
中科院分区：
文献类型：
--
作者：
Dai J;Zhu X;Yoder MC;Wu Y;Colman RW
劈裂高分子量激肽原（HKa）是血浆激肽肽-激肽系统的一种激活产物，可抑制内皮细胞的功能。我们质疑HKa是否会影响内皮祖细胞（EPCs）的功能并加速其衰老。用HKa处理两周可显著抑制大菌落的形成和内皮祖细胞在胶原表面的增殖，而HKa不影响胶原介导的内皮祖细胞粘附和存活。同时，处理后的内皮细胞显示扁平和巨细胞形态变化，并形成细胞内液泡。酸性β-半乳糖苷酶染色表明，HKa在培养1周和2周后分别使衰老EPCs增加2倍和3倍。此外，HKa抑制EPCs的端粒酶活性。HKa浓度依赖性地增加细胞内活性氧（ROS）的产生，并显著上调p38激酶磷酸化和衰老分子p16INK4a的表达。p38抑制剂SB203580可减弱hka增强的p16INK4a表达水平。ROS的猝灭或p38激酶的抑制均可阻止hka诱导的EPC衰老。HKa通过激活ROS - p38激酶- p16INK4a信号级联加速EPC衰老的发生。这一新的活性表明HKa可能是EPC衰老的内源诱导剂。
Cleaved high molecular weight kininogen (HKa), an activation product of the plasma kallikrein-kinin system, inhibits endothelial cell functions. We questioned whether HKa affects the function of endothelial progenitor cells (EPCs) and accelerates their senescence. Treatment with HKa for two weeks markedly inhibited the formation of large colonies and proliferation of EPCs on collagen surfaces, whereas HKa did not affect collagen-mediated EPC adhesion and survival. Concomitantly, treated EPCs displayed flattened and giant cell morphological changes with formation of intracellular vacuoles. As determined by acidic β-galactosidase staining, HKa increased senescent EPCs by 2 fold and >3 fold after culture for one and two weeks, respectively. Additionally, HKa suppressed the telomerase activity of EPCs. HKa concentration-dependently increased the generation of intracellular reactive oxygen species (ROS), and markedly upregulated p38 kinase phosphorylation and prosenescence molecule p16INK4a expression. SB203580, a p38 inhibitor attenuated the level of HKa-enhanced p16INK4a expression. Either quenching of ROS or inhibition of p38 kinase prevented HKa-induced EPC senescence. HKa accelerates the onset of EPC senescence by activating the ROS - p38 kinase - p16INK4a signaling cascade. This novel activity of HKa points out the likelihood for HKa serving as an endogenous inducer of EPC senescence.