Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages.
Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages.
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DOI：
10.1161/circresaha.114.302153
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发表时间：
2014-01-31
影响因子：
20.1
通讯作者：
Tabas I
中科院分区：
文献类型：
--
作者：
Wang Y;Wang GZ;Rabinovitch PS;Tabas I
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，缺乏明确的细胞类型特异性体内因果关系研究，潜在促动脉粥样硬化作用的分子机制仍有待确定。探讨巨噬细胞线粒体在动脉粥样硬化形成中的作用及其分子机制。我们首先验证了西方型饮食喂养的Ldlr-/-小鼠作为人类mitoOS-动脉粥样硬化相关性的模型，显示了病变巨噬细胞中mitoOS的标志物，非核氧化DNA损伤，与主动脉根部病变的发展相关。为了研究巨噬细胞线粒体OS的重要性，我们使用了一种基因工程策略，其中OS抑制剂过氧化氢酶在巨噬细胞的线粒体（mCAT）中异位表达。在这些小鼠中，病变巨噬细胞中的MitoOS被成功抑制，这导致主动脉根部病变面积显著减少。mCAT病变具有较少的单核细胞源性细胞，较少的Ly 6chi单核细胞浸润到病变中，以及较低水平的单核细胞趋化蛋白-1（MCP-1）。病变MCP-1的减少与其他炎症标志物的抑制以及RelA（NF-κB p65）磷酸化的减少有关，表明促炎NF-κB途径的激活减少。使用培养的巨噬细胞中的mitoOS模型，我们表明mCAT通过降低Iκ-激酶-RelA NF-κB途径的活化来抑制MCP-1表达。病变巨噬细胞中的MitoOS通过促进NF-κ B介导的单核细胞进入和其他炎症过程来放大动脉粥样硬化病变的发展。鉴于人类动脉粥样硬化中的线粒体-动脉粥样硬化联系，这些发现揭示了预防动脉粥样硬化进展的潜在新治疗靶点。
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 pro-atherogenic effects remain to be determined. To assess the importance of macrophage mitoOS in atherogenesis and explore the underlying molecular mechanisms. We first validated Western-type diet-fed Ldlr-/- mice as a model of human mitoOS-atherosclerosis association by showing that a marker of mitoOS in lesional macrophages, non-nuclear oxidative DNA damage, 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 Ly6chi monocyte infiltration into lesions, and lower levels of the monocyte chemotactic protein-1 (MCP-1). The decrease in lesional MCP-1 was associated with suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the pro-inflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed MCP-1 expression by decreasing activation of the Iκ-kinase-RelA NF-κB pathway. 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.