CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Sci Rep. 2018 Mar 14;8(1):4501. doi: 10.1038/s41598-018-22819-3.
ShcA is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases and of the Low Density Lipoprotein-related receptor 1 (LRP1), a trans-membrane receptor that protects against atherosclerosis. Here, we examined the role of endothelial ShcA in atherosclerotic lesion formation. We found that atherosclerosis progression was markedly attenuated in mice deleted for ShcA in endothelial cells, that macrophage content was reduced at the sites of lesions, and that adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) were severely reduced. Our data indicate that transcriptional regulation of ShcA by the zinc-finger E-box-binding homeobox 1 (ZEB1) and the Hippo pathway effector YAP, promotes ICAM-1 expression independently of p-NF-κB, the primary driver of adhesion molecules expressions. In addition, ShcA suppresses endothelial Akt and nitric oxide synthase (eNOS) expressions. Thus, through down regulation of eNOS and ZEB1-mediated ICAM-1 up regulation, endothelial ShcA promotes monocyte-macrophage adhesion and atherosclerotic lesion formation. Reducing ShcA expression in endothelial cells may represent an obvious therapeutic approach to prevent atherosclerosis.
ShcA 是一种衔接蛋白，可与受体酪氨酸激酶和低密 度脂蛋白相关受体 1（LRP1）的胞质尾部结合，LRP1 是一种跨膜受体，可防止动脉粥样硬化。在这里，我们研究了内皮细胞 ShcA 在动脉粥样硬化病变形成中的作用。我们发现，内皮细胞 ShcA 缺失的小鼠的动脉粥样硬化进展明显减弱，病变部位的巨噬细胞含量减少，细胞间黏附分子-1（ICAM-1）等黏附分子严重减少。我们的数据表明，锌指 E 盒结合同源盒 1（ZEB1）和 Hippo 通路效应物 YAP 通过转录调节 ShcA，可独立于 p-NF-κB（主要的黏附分子表达驱动因子）促进 ICAM-1 的表达。此外，ShcA 抑制内皮细胞中的 Akt 和一氧化氮合酶（eNOS）的表达。因此，通过下调 eNOS 和 ZEB1 介导的 ICAM-1 上调，内皮细胞 ShcA 促进单核细胞-巨噬细胞黏附并形成动脉粥样硬化病变。降低内皮细胞中的 ShcA 表达可能是预防动脉粥样硬化的一种明显的治疗方法。
