Gareus Ralph, Kotsaki Elena, Xanthoulea Sofia, van der Made Ingeborg, Gijbels Marion J J, Kardakaris Rozina, Polykratis Apostolos, Kollias George, de Winther Menno P J, Pasparakis Manolis
Institute of Genetics, Centre for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47, 50674 Cologne, Germany.
Cell Metab. 2008 Nov;8(5):372-83. doi: 10.1016/j.cmet.2008.08.016.
Atherosclerosis is a progressive disorder of the arterial wall and the underlying cause of cardiovascular diseases such as heart attack and stroke. Today, atherosclerosis is recognized as a complex disease with a strong inflammatory component. The nuclear factor-kappaB (NF-kappaB) signaling pathway regulates inflammatory responses and has been implicated in atherosclerosis. Here, we addressed the function of NF-kappaB signaling in vascular endothelial cells in the pathogenesis of atherosclerosis in vivo. Endothelium-restricted inhibition of NF-kappaB activation, achieved by ablation of NEMO/IKKgamma or expression of dominant-negative IkappaBalpha specifically in endothelial cells, resulted in strongly reduced atherosclerotic plaque formation in ApoE(-/-) mice fed with a cholesterol-rich diet. Inhibition of NF-kappaB abrogated adhesion molecule induction in endothelial cells, impaired macrophage recruitment to atherosclerotic plaques, and reduced expression of cytokines and chemokines in the aorta. Thus, endothelial NF-kappaB signaling orchestrates proinflammatory gene expression at the arterial wall and promotes the pathogenesis of atherosclerosis.
动脉粥样硬化是一种动脉壁的进行性疾病，是心脏病发作和中风等心血管疾病的根本原因。如今，动脉粥样硬化被认为是一种具有强烈炎症成分的复杂疾病。核因子-κB（NF-κB）信号通路调节炎症反应，并与动脉粥样硬化有关。在此，我们探讨了NF-κB信号在体内动脉粥样硬化发病机制中血管内皮细胞的功能。通过敲除NEMO/IKKγ或在内皮细胞中特异性表达显性负性IκBα来实现内皮细胞特异性抑制NF-κB激活，结果在喂食富含胆固醇饮食的ApoE（-/-）小鼠中，动脉粥样硬化斑块形成显著减少。抑制NF-κB可消除内皮细胞中黏附分子的诱导，损害巨噬细胞向动脉粥样硬化斑块的募集，并降低主动脉中细胞因子和趋化因子的表达。因此，内皮NF-κB信号协调动脉壁上的促炎基因表达并促进动脉粥样硬化的发病机制。
