From the Department of Medicine (S.M.E., H.J., E.C., Y.L., N.S., C.S., G.K., A.B., A.B., P.E., M.G.D., G.K.H., G.P.-B., L.M.) and Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (G.K., C.Ö., A.R., T.R., L.P.M., U.H.); Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL (C.Ö.); Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf, Germany (T.R.); Department of Vascular and Endovascular Surgery, Technical University Munich and DZHK Partner Site Munich, Germany (H.H.E., J.P., L.M.); Heart Center, Georg-August-University Göttingen, Germany (I.N.S., U.R.); and Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA (N.J.L.).
Circ Res. 2017 Feb 17;120(4):633-644. doi: 10.1161/CIRCRESAHA.116.309318. Epub 2016 Nov 28.
In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets.
To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke.
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 reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, 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 miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease.
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.
在寻找血管疾病的标志物和调节因子的过程中，microRNAs（miRNAs）已成为有潜力的治疗靶点。
研究处于中风风险的不稳定颈动脉狭窄患者中具有临床意义的 miRNAs。
利用来自 BiKE（卡洛夫斯卡内膜切除术生物库）的患者标本，我们对稳定与不稳定颈动脉斑块患者的血浆 miRNA 表达进行了分析。基于聚合酶链反应的血浆 miRNA 阵列，在颈动脉病变部位取样，鉴定出 8 种失调的 miRNA（miR-15b、miR-29c、miR-30c/d、miR-150、miR-191、miR-210 和 miR-500）。miR-210 在局部血浆中下调最为显著。激光捕获显微切割和原位杂交显示 miR-210 在纤维帽中有明显的定位。我们证实 miR-210 可直接靶向肿瘤抑制基因 APC（结肠腺瘤性息肉），从而影响 Wnt（无翅型整合位点）信号通路并调节平滑肌细胞存活和晚期动脉粥样硬化病变中的分化。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 的明显变化。体外和体内调节 miR-210 可改善纤维帽稳定性，从而影响血管疾病。
处于中风风险的不稳定颈动脉斑块的特征是 miR-210 表达降低。miR-210 通过抑制 APC 促进颈动脉斑块稳定，确保平滑肌细胞存活。我们提出局部递送 miR-210 作为预防动脉血栓形成性血管事件的治疗方法。
