Disturbed Blood Flow Induces RelA Expression via c-Jun N-Terminal Kinase 1 A Novel Mode of NF-κB Regulation That Promotes Arterial Inflammation
Disturbed Blood Flow Induces RelA Expression via c-Jun N-Terminal Kinase 1 A Novel Mode of NF-κB Regulation That Promotes Arterial Inflammation
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DOI：
10.1161/circresaha.110.233841
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发表时间：
2011-04-15
影响因子：
20.1
通讯作者：
Evans, Paul C.
中科院分区：
文献类型：
--
作者：
Cuhlmann, Simon;Van der Heiden, Kim;Evans, Paul C.
理由：核因子(NF)- κ B通路参与动脉炎症。虽然调控NF-kappa B转录激活的信号通路已经明确，但调控NF-kappa B转录因子表达水平的机制尚不确定。目的：研究内皮细胞（ECs）中RelA NF-kappa B亚基表达的信号调控机制及其在动脉炎症中的作用。方法和结果：基因沉默和染色质免疫沉淀显示，c-Jun n -末端激酶（JNK）和下游转录因子ATF2在ECs中正调控RelA的表达。我们得出结论，这一途径促进局灶性动脉炎症，因为JNK1的基因缺失减少了NF-kappa B的表达和巨噬细胞在动脉粥样硬化易感部位的积累。我们假设JNK对NF-kappa B的信号传导可能受到机械力的控制，因为动脉粥样硬化易感性与暴露于血流紊乱有关。这是通过使用收缩袖带修饰的颈动脉正电子发射断层成像来评估的，这是一种研究体内血流紊乱对血管生理影响的方法。这种方法与面部染色相结合，发现血流紊乱会通过JNK1提高小鼠颈动脉中NF-kappa B的表达和炎症。结论：我们证明，血流紊乱通过JNK-ATF2信号诱导内皮细胞中NF-kappa B的表达，从而促进动脉炎症。因此，我们的研究结果阐明了JNK-NF-kappa B串扰的一种新形式，它可能决定了动脉炎症和动脉粥样硬化的局灶性。（Circ Res. 2011;108:950-959）
Rationale: The nuclear factor (NF)-kappa B pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-kappa B are defined, the mechanisms that regulate the expression levels of NF-kappa B transcription factors are uncertain.Objective: We studied the signaling mechanisms that regulate RelA NF-kappa B subunit expression in endothelial cells (ECs) and their role in arterial inflammation.Methods and Results: Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-kappa B expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-kappa B may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-kappa B expression and inflammation in murine carotid arteries via JNK1.Conclusions: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-kappa B expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-kappa B crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis. (Circ Res. 2011;108:950-959.)