MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions
MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions
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DOI：
10.1161/circresaha.116.309318
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发表时间：
2017-02-01
影响因子：
20.1
通讯作者：
Maegdefessel, Lars
中科院分区：
文献类型：
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作者：
Eken, Suzanne M.;Jin, Hong;Maegdefessel, Lars
基本原理：在寻找血管疾病的标志物和调节剂，microRNAs（miRNAs）已成为有效的治疗targets.Objective：探讨miRNAs在不稳定的颈动脉狭窄患者中风的风险中的临床意义，方法和结果：使用患者的材料从BiKE（生物银行Karolinska Endarterectomies），我们分析了稳定与不稳定的颈动脉斑块患者的miRNA表达。在颈动脉病变部位采集的血浆中，基于聚合酶链反应的miRNA阵列鉴定出8种失调的miRNA（miR-15 b、miR-29 c、miR-30 c/d、miR-150、miR-191、miR-210和miR-500）。miR-210是局部血浆材料中最显著下调的miRNA。激光捕获显微切割和原位杂交揭示了miR-210在纤维帽中的独特定位。我们证实miR-210直接靶向肿瘤抑制基因APC（腺瘤性结肠息肉病），从而影响Wnt（无翼相关整合位点）信号传导并调节平滑肌细胞存活，以及晚期动脉粥样硬化病变的分化。在2种血管重塑和斑块破裂的啮齿动物模型中可检测到动脉miR-210的实质性变化。调节miR-210在体外和体内改善纤维帽稳定性与血管diseases.Conclusions的影响：一个不稳定的颈动脉斑块中风的风险，其特点是低表达的miR-210。miR-210有助于通过抑制APC稳定颈动脉斑块，确保平滑肌细胞存活。我们提出局部递送miR-210作为预防动脉粥样硬化血栓形成血管事件的治疗方法。
Rationale: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets.Objective: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke.Methods and Results: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reactionbased miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease.Conclusions: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.