Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis.
Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis.
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DOI：
10.1016/j.atherosclerosis.2012.04.010
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发表时间：
2012-12
期刊：
影响因子：
5.3
通讯作者：
Velazquez, Omaida C.
中科院分区：
文献类型：
--
作者：
Liu, Zhao-Jun;Tan, Yurong;Beecham, Gary W.;Seo, David M.;Tian, Runxia;Li, Yan;Vazquez-Padron, Roberto I.;Pericak-Vance, Margaret;Vance, Jeffery M.;Goldschmidt-Clermont, Pascal J.;Livingstone, Alan S.;Velazquez, Omaida C.
Notch信号在血管疾病的发病机制中起着关键作用。然而，很少有人知道它在动脉粥样硬化中的作用。我们试图研究Notch信号在动脉粥样硬化中的潜在参与。用免疫组化方法检测Notch通路组分在有或无动脉粥样硬化斑块的小鼠和人主动脉中的表达。用PCR阵列和免疫印迹法检测Notch靶基因在年轻和老年人内皮细胞（EC）中的表达。利用体外功能丧失和获得方法通过ProteinArray评估Notch信号传导在诱导EC衰老和促炎细胞因子分泌中的作用。对1054例冠状动脉疾病（CAD）患者的血液样本进行了Notch基因谱研究。使用全基因组单核苷酸多态性（SNP）阵列进行基因分型。Notch途径组分在小鼠和人动脉粥样硬化病变的管腔EC中上调。此外，Notch通路在老年人EC中被激活，而在年轻人EC中则没有。增强的Notch激活导致EC衰老，并显著上调与炎症反应有关的几种分子（IL-6/IL-8/IL-1α/RANTES/ICAM-1）的表达。上调的IL-6是介导白细胞跨内皮迁移的部分原因。遗传关联分析检测到，在分析的6个Notch通路基因的82个SNP中，4个SNP与CAD负担具有名义关联。Notch通路在动脉粥样硬化斑块处的管腔EC中被激活，并导致EC的促炎反应和衰老。Notch信号可能与人类CAD风险有关。这些发现暗示了Notch信号传导在动脉粥样硬化中的潜在参与。
Notch signaling plays pivotal roles in the pathogenesis of vascular disease. However, little is known about its role in atherosclerosis. We sought to investigate the potential involvement of the Notch signaling in atherosclerosis. Expression of Notch pathway components in mouse and human aorta with or without atherosclerosis plaque was examined by immuno-histochemistry. Expression of Notch target genes in young versus aged human endothelial cells (EC) was examined by PCRArray and immunoblot. In vitro loss- and gain-of-function approaches were utilized to evaluate the role of Notch signaling in inducing EC senescence and secretion of pro-inflammatory cytokines by ProteinArray. Notch gene profile was studied in 1054 blood samples of patients with coronary artery disease (CAD). Genotyping was performed using the Genome-Wide Single Nucleotide Polymorphism (SNP) Array. Notch pathway components were upregulated in luminal EC at atherosclerotic lesions from mouse and human aortas. In addition, the Notch pathway was activated in aged but not young human EC. Enforced Notch activation resulted in EC senescence and significantly upregulated expression of several molecules implicated in the inflammatory response (IL-6/IL-8/IL-1α/RANTES/ICAM-1). The upregulated IL-6 was partially responsible for mediating leukocyte transendothelial migration. Genetic association analysis detected, of 82 SNPs across 6 Notch pathway genes analyzed, 4 SNPs with nominal association with CAD burden. Notch pathway is activated in luminal EC at atherosclerotic plaques and results in pro-inflammatory response and senescence of EC. Notch signaling may be linked to human CAD risk. These findings implicate a potential involvement of Notch signaling in atherosclerosis.
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影响因子：
37.8
作者：
Goldschmidt-Clermont, PJ;Creager, MA;Dzau, VJ
通讯作者：
Dzau, VJ
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：
4.8
作者：
Liu, ZJ;Snyder, R;Velazquez, OC
通讯作者：
Velazquez, OC
动脉粥样硬化的炎症。
DOI：
10.1161/atvbaha.108.179705
发表时间：
2012-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Libby P
通讯作者：
Libby P
影响因子：
15.9
作者：
Balint, K;Xiao, M;Liu, ZJ
通讯作者：
Liu, ZJ