Reelin Depletion Protects Against Atherosclerosis by Decreasing Vascular Adhesion of Leukocytes.
Reelin Depletion Protects Against Atherosclerosis by Decreasing Vascular Adhesion of Leukocytes.
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DOI：
10.1161/atvbaha.121.316000
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Herz J
中科院分区：
文献类型：
--
作者：
Calvier L;Xian X;Lee RG;Sacharidou A;Mineo C;Shaul PW;Kounnas MZ;Tsai S;Herz J
Reelin及其受体Apoer 2通过促进白细胞-内皮细胞粘附在内皮细胞功能障碍中发挥重要作用，白细胞-内皮细胞粘附是动脉粥样硬化炎症过程的重要组成部分。因此，我们假设，药理学消耗循环Reelin代表一种新的治疗策略，以阻止动脉粥样硬化的进展。体外研究表明，人血浆诱导单核细胞粘附到内皮细胞，而Reelin耗尽血浆对单核细胞粘附没有影响。信号转导分析显示，Reelin激活Dab 2、PI 3 K、Akt和NF-κB级联反应，促进粘附标志物E-选择素、ICAM-1和VCAM-1的表达。活体显微镜检查证实用Reelin反义寡核苷酸（阿索）处理的小鼠中白细胞-内皮粘附减少。在血管平滑肌细胞中，Reelin诱导Stat 3磷酸化以促进细胞增殖，这是动脉粥样硬化斑块进展的另一个标志。为了研究Reelin药物消耗是否可以预防动脉粥样硬化，用Reelin阿索或中和抗体（CR-50）处理喂食高胆固醇饮食的低密度脂蛋白受体缺陷（Ldlr−/−）小鼠，以全身消耗循环Reelin。在两种治疗中，动脉粥样硬化斑块进展均显著减弱。这些体内结果表明，Reelin耗竭降低血管粘附并抑制单核细胞的募集，从而防止斑块进展。这些发现表明，Reelin抑制可能提供一种新的治疗方法，以抵消白细胞或单核细胞粘附以及外渗，并抑制动脉粥样硬化的进展。这种策略也可能与涉及白细胞或单核细胞外渗作为中心病理机制的其他疾病相关，如多发性硬化症或关节炎。
Reelin and its receptor Apoer2 play a prominent role in endothelial cell dysfunction by promoting leukocyte–endothelial cell adhesion, an important component of the inflammatory process underlying atherosclerosis. We therefore hypothesized that pharmacological depletion of circulating Reelin represents a novel therapeutic strategy to impede the progression of atherosclerosis. In vitro studies demonstrated that human plasma induced monocyte adhesion to endothelial cells, while Reelin-depleted plasma had no effect on monocyte adhesion. Signaling analysis revealed that Reelin activated Dab2, PI3K, Akt and NF-κB cascade to promote the expression of adhesion markers (E-selectin, ICAM-1, and VCAM-1). Intravital microscopy confirmed decreased leukocyte-endothelial adhesion in mice treated with Reelin antisense oligonucleotide (ASO). In vascular smooth muscle cells, Reelin induced Stat3 phosphorylation to promote cell proliferation, which is another hallmark of atherosclerotic plaque progression. To investigate if Reelin pharmaceutical depletion protects against atherosclerosis, low-density lipoprotein receptor–deficient (Ldlr−/−) mice fed with high cholesterol diet were treated with either Reelin ASO or neutralizing antibody (CR-50) to systemically deplete circulating Reelin. In both treatments, atherosclerotic plaque progression was markedly attenuated. These in vivo results suggest that Reelin depletion decreases vascular adhesion and inhibits the recruitment of monocytes and consequently prevents plaque progression. These findings suggest that Reelin inhibition may provide a novel therapeutic approach to counteract leukocyte or monocyte adhesion as well as extravasation and inhibit the progression of atherosclerosis. This strategy may also be relevant for other diseases that involve leukocyte or monocyte extravasation as a central pathological mechanism, such as multiple sclerosis or arthritis.