巨噬细胞线粒体氧化应激促进动脉粥样硬化和核因子-κB 介导的巨噬细胞炎症。
Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages.
机构信息
From the Departments of Medicine, Physiology, and Cellular Biophysics, and Pathology and Cell Biology (Y.W., I.T.), and Medical Scientist Training Program (G.Z.W.), Columbia University, New York, NY; and Department of Pathology, University of Washington, Seattle, WA (P.S.R.).
出版信息
Circ Res. 2014 Jan 31;114(3):421-33. doi: 10.1161/CIRCRESAHA.114.302153. Epub 2013 Dec 2.
RATIONALE
Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell type-specific causation studies in vivo are lacking, and the molecular mechanisms of potential proatherogenic effects remain to be determined.
OBJECTIVE
Our aims were to assess the importance of macrophage mitoOS in atherogenesis and to explore the underlying molecular mechanisms.
METHODS AND RESULTS
We first validated Western diet-fed Ldlr(-/-) mice as a model of human mitoOS-atherosclerosis association by showing that non-nuclear oxidative DNA damage, a marker of mitoOS in lesional macrophages, correlates with aortic root lesion development. To investigate the importance of macrophage mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6c(hi) monocyte infiltration into lesions, and lower levels of monocyte chemotactic protein-1. The decrease in lesional monocyte chemotactic protein-1 was associated with the suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the proinflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed monocyte chemotactic protein-1 expression by decreasing the activation of the IκB-kinase β-RelA NF-κB pathway.
CONCLUSIONS
MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-κB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis.
背景
线粒体氧化应激（mitoOS）已被证明与人类动脉粥样硬化的进展相关。然而，体内缺乏明确的细胞类型特异性因果关系研究，潜在的促动脉粥样硬化作用的分子机制仍有待确定。
目的
我们旨在评估巨噬细胞 mitoOS 在动脉粥样硬化形成中的重要性，并探索潜在的分子机制。
方法和结果
我们首先通过显示病变巨噬细胞中非核氧化 DNA 损伤（mitoOS 的标志物）与主动脉根部病变发展相关，验证了西方饮食喂养的 Ldlr（-/-）小鼠是人类 mitoOS-动脉粥样硬化关联的模型。为了研究巨噬细胞 mitoOS 的重要性，我们使用了一种基因工程策略，其中过氧化物酶体抗氧化酶 CAT 在外源表达于巨噬细胞的线粒体中（mCAT）。这些小鼠中病变巨噬细胞中的 mitoOS 被成功抑制，导致主动脉根部病变面积显著减少。mCAT 病变中单核细胞衍生细胞减少，Ly6c（hi）单核细胞浸润到病变中的减少，单核细胞趋化蛋白-1 水平降低。病变单核细胞趋化蛋白-1 的减少与炎症标志物的抑制以及 RelA（NF-κB p65）磷酸化的降低有关，表明促炎 NF-κB 通路的激活减少。通过培养巨噬细胞中的 mitoOS 模型，我们表明 mCAT 通过减少 IκB-激酶β-RelA NF-κB 通路的激活来抑制单核细胞趋化蛋白-1 的表达。
结论
病变巨噬细胞中的 mitoOS 通过促进 NF-κB 介导的单核细胞进入和其他炎症过程，放大动脉粥样硬化病变的发展。鉴于人类粥样斑块中 mitoOS-动脉粥样硬化的联系，这些发现揭示了一个潜在的新的治疗靶点，以防止动脉粥样硬化的进展。
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