Role of extracellular RNA in atherosclerotic plaque formation in mice.
Role of extracellular RNA in atherosclerotic plaque formation in mice.
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DOI：
10.1161/circulationaha.113.002562
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发表时间：
2014-02-04
期刊：
影响因子：
37.8
通讯作者：
Zernecke A
中科院分区：
文献类型：
--
作者：
Simsekyilmaz S;Cabrera-Fuentes HA;Meiler S;Kostin S;Baumer Y;Liehn EA;Weber C;Boisvert WA;Preissner KT;Zernecke A
损伤后的动脉粥样硬化和血管重塑是由炎症和单核细胞浸润驱动的。最近发现细胞外 RNA (eRNA) 在组织损伤部位富集，并充当促炎介质。我们在这里探讨了 eRNA 在高脂饮食 (HFD) 诱导的动脉粥样硬化和动脉粥样硬化易发小鼠损伤后新内膜形成中的作用。在 HFD 喂养的低密度脂蛋白受体缺陷 (Ldlr−/−) 小鼠的动脉粥样硬化病变中，以时间渐进的方式揭示了 eRNA 的存在。血浆中的 RNase 活性在前 2 周内增加（44 ± 9 vs. 70 ± 7 mU/mg 蛋白质；p=0.0012），随后在 HFD 4 周后降至基线以下水平（44 ± 9 vs. 12 ± 2 mU/mg 蛋白质；p<0.0001）。骨髓源性巨噬细胞暴露于 eRNA 会导致促炎介质肿瘤坏死因子-α、精氨酸酶-2、白细胞介素 (IL)-1β、IL-6 和干扰素-γ 浓度依赖性上调。在载脂蛋白 E 缺陷 (apoE−/−) 小鼠动脉损伤后加速动脉粥样硬化模型中，RNase1 治疗可降低血浆 eRNA 水平的升高，这一点在损伤后得到证实。同样，与媒介物处理的 apoE−/− 对照相比，RNase1 给药减少了新内膜形成（25.0 ± 6.2 与 46.9 ± 6.9 × 103 µm2，p=0.0339），并且与斑块巨噬细胞含量显着减少相关。从功能上讲，RNase1 治疗会损害体外流动条件下激活的平滑肌细胞上的单核细胞停滞，并抑制体内白细胞向受损颈动脉的募集。由于 eRNA 与动脉粥样硬化病变相关，并有助于动脉粥样硬化易发小鼠的炎症依赖性斑块进展，因此以 RNase1 为靶点的 eRNA 可能成为对抗动脉粥样硬化的新治疗选择。
Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage, and to act as a pro-inflammatory mediator. We here addressed the role of eRNA in high-fat-diet (HFD)-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice. The presence of eRNA was revealed in atherosclerotic lesions from HFD-fed low density lipoprotein receptor-deficient (Ldlr−/−) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44 ± 9 vs. 70 ± 7 mU/mg protein; p=0.0012), followed by a decrease to levels below baseline after 4 weeks of HFD (44 ± 9 vs. 12 ± 2 mU/mg protein; p<0.0001). Exposure of bone marrow-derived macrophages to eRNA resulted in a concentration-dependent upregulation of the pro-inflammatory mediators tumor necrosis factor-α, arginase-2, Interleukin (IL)-1β, IL-6 and Interferon-γ. In a model of accelerated atherosclerosis after arterial injury in apolipoprotein E-deficient (apoE−/−) mice, treatment with RNase1 diminished the increased plasma level of eRNA, evidenced after injury. Likewise, RNase1 administration reduced neointima formation compared to vehicle-treated apoE−/− controls (25.0 ± 6.2 vs. 46.9 ± 6.9 × 103 µm2, p=0.0339), and was associated with a significant decrease in plaque macrophage content. Functionally, RNase1 treatment impaired monocyte arrest on activated smooth muscle cells under flow conditions in vitro, and inhibited leukocyte recruitment to injured carotid arteries in vivo. As eRNA is associated with atherosclerotic lesions and contributes to inflammation-dependent plaque progression in atherosclerosis-prone mice, its targeting with RNase1 may serve as a new treatment option against atherosclerosis.