Netrin-1: Focus on its role in cardiovascular physiology and atherosclerosis.

IF 1.5 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS
JRSM Cardiovascular Disease Pub Date : 2020-11-25 eCollection Date: 2020-01-01 DOI:10.1177/2048004020959574
Vasco Claro, Albert Ferro
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引用次数: 0

Abstract

The netrins form a family of laminin-related proteins which were first described as modulators of cell migration and axonal guidance during fetal development. Netrin-1 is the most extensively studied member of this family and, since its discovery, non-neural roles have been associated with it. Together with its receptors, DCC/neogenin and UNC5, netrin-1 has been shown to be involved in the regulation of angiogenesis, organogenesis, cancer and inflammation. An NF-κB-dependent truncated isoform of netrin-1 has also been shown to be produced in endothelial and some types of cancer cells, which both accumulates in and affects the function of the nucleus. In atherosclerosis, conflicting roles for netrin-1 have been reported on plaque progression via its receptor UNC5b. Whereas endothelial-derived netrin-1 inhibits chemotaxis of leukocytes and reduces the migration of monocytes to the atherosclerotic plaque, netrin-1 expressed by macrophages within the plaque plays a pro-atherogenic role, promoting cell survival, recruiting smooth muscle cells and inhibiting foam cell egress to the lymphatic system. In contrast, there is evidence that netrin-1 promotes macrophage differentiation to an alternative activated phenotype and induces expression of IL-4 and IL-13, while downregulate expression of IL-6 and COX-2. Further work is needed to elucidate the precise roles of the two isoforms of netrin-1 in different cell types in the context of atherosclerosis, and its potential as a putative novel therapeutic target in this disease.

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Netrin-1:在心血管生理和动脉粥样硬化中的作用
网状蛋白形成一个与层粘连蛋白相关的蛋白家族,最初被描述为胎儿发育过程中细胞迁移和轴突引导的调节剂。Netrin-1是该家族中研究最广泛的成员,自发现以来,非神经功能与它有关。netrin-1及其受体DCC/neogenin和UNC5已被证明参与血管生成、器官生成、癌症和炎症的调节。内皮细胞和某些类型的癌细胞中也会产生依赖NF-κ b的netrin-1的截断异构体,这种异构体在细胞核中积聚并影响细胞核的功能。在动脉粥样硬化中,netrin-1通过其受体UNC5b在斑块进展中的作用相互矛盾。内皮来源的netrin-1抑制白细胞的趋化性并减少单核细胞向动脉粥样硬化斑块的迁移,而斑块内巨噬细胞表达的netrin-1起促动脉粥样硬化作用,促进细胞存活,招募平滑肌细胞并抑制泡沫细胞向淋巴系统的迁移。相反,有证据表明netrin-1促进巨噬细胞分化为另一种活化表型,诱导IL-4和IL-13的表达,同时下调IL-6和COX-2的表达。需要进一步的工作来阐明netrin-1的两种亚型在动脉粥样硬化背景下不同细胞类型中的确切作用,以及它作为该疾病假定的新治疗靶点的潜力。
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来源期刊
JRSM Cardiovascular Disease
JRSM Cardiovascular Disease CARDIAC & CARDIOVASCULAR SYSTEMS-
自引率
6.20%
发文量
12
审稿时长
12 weeks
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