Institute for Molecular Cardiovascular Research, RWTH University Hospital Aachen, Aachen, Germany (S.S., E.A.L.); Department of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany (H.A.C.-F., K.T.P.); Department of Microbiology, Kazan Federal University, Kazan, Russian Federation (H.A.C.-F.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI (S.M., Y.B., W.A.B.); Core Lab for Molecular and Structural Biology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (S.K.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (C.W., A.Z.); Rudolf Virchow Center and Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg, University of Würzburg, Würzburg, Germany (A.Z.); and Department of Vascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany (A.Z.).
Circulation. 2014 Feb 4;129(5):598-606. doi: 10.1161/CIRCULATIONAHA.113.002562. Epub 2013 Nov 7.
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 proinflammatory mediator. Here, we addressed the role of eRNA in high-fat diet-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice.
The presence of eRNA was revealed in atherosclerotic lesions from high-fat diet-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 versus 70±7 mU/mg protein; P=0.0012), followed by a decrease to levels below baseline after 4 weeks of high-fat diet (44±9 versus 12±2 mU/mg protein; P<0.0001). Exposure of bone marrow-derived macrophages to eRNA resulted in a concentration-dependent upregulation of the proinflammatory mediators tumor necrosis factor-α, arginase-2, interleukin-1β, interleukin-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 in comparison with vehicle-treated ApoE(-/-) controls (25.0±6.2 versus 46.9±6.9×10(3) μm(2), 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.
Because 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.
动脉粥样硬化和损伤后的血管重塑是由炎症和单核细胞浸润驱动的。最近有研究表明，细胞外 RNA（eRNA）在组织损伤部位富集，并作为一种促炎介质发挥作用。在此，我们研究了 eRNA 在高脂饮食诱导的动脉粥样硬化和动脉粥样硬化易感小鼠损伤后新生内膜形成中的作用。
在高脂饮食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，eRNA 的存在呈时间进展性。血浆中的核糖核酸酶活性在最初的 2 周内增加（44±9 与 70±7 mU/mg 蛋白；P=0.0012），随后在 4 周的高脂饮食后降至基线以下（44±9 与 12±2 mU/mg 蛋白；P<0.0001）。骨髓来源的巨噬细胞暴露于 eRNA 后，促炎介质肿瘤坏死因子-α、精氨酸酶-2、白细胞介素-1β、白细胞介素-6 和干扰素-γ的表达呈浓度依赖性上调。在载脂蛋白 E 缺陷（ApoE（-/-））小鼠动脉损伤后的加速动脉粥样硬化模型中，用核糖核酸酶 1 处理可减少损伤后血浆中 eRNA 水平的升高。同样，与用载体处理的 ApoE（-/-）对照相比，RNase1 给药可减少新生内膜形成（25.0±6.2 与 46.9±6.9×10（3）μm（2），P=0.0339），并与斑块内巨噬细胞含量的显著降低相关。功能上，RNase1 处理可损害体外流动条件下单核细胞在激活的平滑肌细胞上的阻滞，并抑制体内损伤颈动脉白细胞募集。
由于 eRNA 与动脉粥样硬化病变相关，并促进动脉粥样硬化易感小鼠中炎症依赖性斑块进展，因此用 RNase1 靶向治疗可能成为一种新的抗动脉粥样硬化治疗选择。
