OBJECTIVE Netrin-1 has been shown to play a role in the initiation of atherosclerosis in mice models. However, little is known about the role of Netrin-1 in humans. We set out to study whether Netrin-1 is associated with different stages of atherosclerosis. Approach and Results: Plasma Netrin-1 levels were measured in different patient cohorts: (1) 22 patients with high cardiovascular risk who underwent arterial wall inflammation assessment using positron-emission tomography / computed tomography, (2) 168 patients with a positive family history of premature atherosclerosis in whom coronary artery calcium scores were obtained, and (3) 104 patients with chest pain who underwent coronary computed tomography angiography imaging to evaluate plaque vulnerability and burden. Netrin-1 plasma levels were negatively correlated with arterial wall inflammation (β, -0.01 [95% CI, 0.02 to -0.01] R2, 0.61; P<0.0001), and concentrations of Netrin-1 were significantly lower when atherosclerosis was present compared with individuals without atherosclerosis (28.01 versus 10.51 ng/mL, P<0.001). There was no difference in Netrin-1 plasma concentrations between patients with stable versus unstable plaques (11.17 versus 11.74 ng/mL, P=0.511). However, Netrin-1 plasma levels were negatively correlated to total plaque volume (β, -0.09 [95% CI, -0.11 to -0.08] R2, 0.57, P<0.0001), calcified plaque volumes (β, -0.10 [95% CI, -0.12 to -0.08] R2, 0.53; P<0.0001), and noncalcified plaque volumes (β, -0.08 [95% CI, -0.10 to -0.06] R2, 0.41; P<0.0001). Treatment of inflammatory stimulated endothelial cells with plasma with high Netrin-1 level resulted in reduced endothelial inflammation and consequently, less monocyte adhesion. CONCLUSIONS Netrin-1 plasma levels are lower in patients with subclinical atherosclerosis and in patients with arterial wall inflammation. Netrin-1 is not associated with plaque vulnerability; however, it is negatively correlated to plaque burden, suggesting that Netrin-1 is involved in some, but not all, stages of atherosclerosis.

中文翻译：

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Netrin-1与人类的动脉粥样硬化程度呈反相关。

目的Netrin-1已显示在小鼠模型中引发动脉粥样硬化中发挥作用。但是，关于Netrin-1在人类中的作用知之甚少。我们着手研究Netrin-1是否与动脉粥样硬化的不同阶段有关。方法和结果：在不同的患者队列中测量血浆Netrin-1水平：（1）22例心血管疾病高风险患者接受正电子发射断层扫描/计算机断层扫描进行动脉壁炎症评估，（2）168例家族史阳性的患者获得冠状动脉钙化评分的过早的动脉粥样硬化；（3）104例胸痛患者接受了冠状动脉计算机断层摄影血管造影成像，以评估斑块易损性和负担。Netrin-1血浆水平与动脉壁炎症反应呈负相关（β，-0.01 [95％CI，0.02至-0.01] R2，0.61； P <0.0001），当存在动脉粥样硬化时，Netrin-1的浓度显着降低无动脉粥样硬化的个体（28.01对10.51 ng / mL，P <0.001）。斑块稳定和不稳定的患者之间的Netrin-1血浆浓度没有差异（11.17对11.74 ng / mL，P = 0.511）。但是，Netrin-1血浆水平与总斑块体积（β，-0.09 [95％CI，-0.11至-0.08] R2、0.57，P <0.0001），钙化斑块体积（β，-0.10 [95％ CI，-0.12至-0.08] R2，0.53； P ＜0.0001）和未钙化的斑块体积（β，-0.08 [95％CI，-0.10至-0.06] R2，0.41； P ＜0.0001）。用高Netrin-1水平的血浆处理炎症刺激的内皮细胞可减少内皮炎症，从而减少单核细胞的粘附。结论在亚临床动脉粥样硬化患者和动脉壁炎症患者中，Netrin-1血浆水平较低。Netrin-1与斑块漏洞无关；但是，它与斑块负荷负相关，表明Netrin-1参与了部分但并非全部动脉粥样硬化阶段。