Copper chelation represses the vascular response to injury
Copper chelation represses the vascular response to injury
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DOI：
10.1073/pnas.1231994100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Maciag, T
中科院分区：
文献类型：
--
作者：
Mandinov, L;Mandinova, A;Maciag, T
诱导急性炎症反应，随后从外周血单核细胞释放多肽细胞因子和生长因子，介导对血管损伤的反应。由于Cu2+结合蛋白il -1 α和成纤维细胞生长因子1以应激依赖的方式通过细胞内Cu2+促进S100A13异四聚体复合物的形成，并且这些信号无肽多肽在体内被认为是血管损伤的调节剂，因此我们研究了Cu2+螯合抑制损伤后新内膜增厚的能力。我们观察到，口服Cu2+螯合剂四硫钼酸盐能够减少大鼠球囊损伤后的内膜增厚。有趣的是，尽管对照新生内膜切片的免疫组织化学分析显示MAC1、il -1 α、S100A13和酸性磷脂酰丝氨酸的显著染色，但四硫钼酸盐处理动物的类似切片却没有。此外，血管损伤期间IL-1受体拮抗剂的腺病毒基因转移也显著减少了新内膜增厚的面积。我们的数据表明，细胞内铜可能通过体外人外周血单核细胞的非经典输出机制调节应激诱导的il - 1a释放，从而参与体内对损伤的介导反应。
The induction of an acute inflammatory response followed by the release of polypeptide cytokines and growth factors from peripheral blood monocytes has been implicated in mediating the response to vascular injury. Because the Cu2+-binding proteins IL-1alpha and fibroblast growth factor 1 are exported into the extracellular compartment in a stress-dependent manner by using intracellular Cu2+ to facilitate the formation of S100A13 heterotetrameric complexes and these signal peptideless polypeptides have been implicated as regulators of vascular injury in vivo, we examined the ability of Cu2+ chelation to repress neointimal thickening in response to injury. We observed that the oral administration of the Cu2+ chelator tetrathiomolybdate was able to reduce neointimal thickening after balloon injury in the rat. Interestingly, although immunohistochemical analysis of control neointimal sections exhibited prominent staining for MAC1, IL-1alpha, S100A13, and the acidic phospholipid phosphatidylserine, similar sections obtained from tetrathiomolybdate-treated animals did not. Further, adenoviral gene transfer of the IL-1 receptor antagonist during vascular injury also significantly reduced the area of neointimal thickening. Our data suggest that intracellular copper may be involved in mediating the response to injury in vivo by its ability to regulate the stress-induced release of IL-1 a by using the nonclassical export mechanism employed by human peripheral blood mononuclear cells in vitro.