Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation.
Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation.
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DOI：
10.1126/scisignal.aad5578
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发表时间：
2016-03-15
影响因子：
7.3
通讯作者：
Herz J
中科院分区：
文献类型：
--
作者：
Ding Y;Huang L;Xian X;Yuhanna IS;Wasser CR;Frotscher M;Mineo C;Shaul PW;Herz J
多模块糖蛋白 Reelin 通过与神经元上的载脂蛋白 E 受体 2 (Apoer2) 和极低密度脂蛋白受体 (Vldlr) 结合来控制神经元迁移和突触传递。在外周，Reelin由肝脏产生，在血液中循环，促进血栓形成和止血。为了研究 Reelin 是否影响动脉粥样硬化形成，我们研究了易发生动脉粥样硬化的低密度脂蛋白受体缺陷 (Ldlr−/−) 小鼠，在这些小鼠中，我们诱导性地普遍或仅在肝脏中删除了 Reelin，从而阻止了循环 Reelin 的产生。在两种类型的 Reelin 缺陷小鼠中，动脉粥样硬化进展均显着减弱，动脉粥样硬化病变部位的巨噬细胞含量以及血管细胞粘附分子-1 (VCAM1) 和细胞间粘附分子-1 (ICAM1) 的内皮细胞染色减少。活体显微镜检查显示，Reelin 缺陷小鼠的白细胞-内皮粘附力降低。在培养的人内皮细胞中，Reelin 通过抑制内皮一氧化氮合酶 (eNOS) 活性并以 Apoer2 依赖性方式增加 NF-kB 活性，增强单核细胞粘附并增加 ICAM-1、VCAM-1 和 E-选择素表达。这些发现表明，循环中的 Reelin 通过增加血管炎症来促进动脉粥样硬化，减少或抑制循环中的 Reelin 可能为预防心血管疾病提供一种新方法。
The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to Apolipoprotein E receptor-2 (Apoer2) and very low-density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis we studied atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr−/−) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM-1, VCAM-1 and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing the activity of NF-kB in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.
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影响因子：
7.3
作者：
Lane-Donovan C;Philips GT;Wasser CR;Durakoglugil MS;Masiulis I;Upadhaya A;Pohlkamp T;Coskun C;Kotti T;Steller L;Hammer RE;Frotscher M;Bock HH;Herz J
通讯作者：
Herz J
影响因子：
5.3
作者：
DArcangelo, G;Nakajima, K;Curran, T
通讯作者：
Curran, T
影响因子：
5.3
作者：
Beffert, U;Durudas, A;Herz, J
通讯作者：
Herz, J
DOI：
10.1073/pnas.0908176106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Durakoglugil, Murat S.;Chen, Ying;Herz, Joachim
通讯作者：
Herz, Joachim
影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J