Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.
Cardiovasc Res. 2017 Apr 1;113(5):498-507. doi: 10.1093/cvr/cvx015.
The lectin-like oxLDL receptor-1 (LOX-1) promotes endothelial uptake of oxidized low-density lipoprotein (oxLDL) and plays an important role in atherosclerosis and acute coronary syndromes (ACS). However, its role in arterial thrombus formation remains unknown. We investigated whether LOX-1 plays a role in arterial thrombus formation in vivo at different levels of oxLDL using endothelial-specific LOX-1 transgenic mice (LOX-1TG) and a photochemical injury thrombosis model of the carotid artery.
In mice fed a normal chow diet, time to arterial occlusion was unexpectedly prolonged in LOX-1TG as compared to WT. In line with this, tissue factor (TF) expression and activity in carotid arteries of LOX-1TG mice were reduced by half. This effect was mediated by activation of octamer transcription factor 1 (Oct-1) leading to upregulation of the mammalian deacetylase silent information regulator-two 1 (SIRT1) via binding to its promoter and subsequent inhibition of NF-κB signaling. In contrast, intravenous injection of oxLDL as well as high cholesterol diet for 6 weeks led to a switch from the Oct-1/SIRT1 signal transduction pathway to the ERK1/2 pathway and in turn to an enhanced thrombotic response with shortened occlusion time.
Thus, LOX-1 differentially regulates thrombus formation in vivo depending on the degree of activation by oxLDL. At low oxLDL levels LOX-1 activates the protective Oct-1/SIRT1 pathway, while at higher levels of the lipoprotein switches to the thrombogenic ERK1/2 pathway. These findings may be important for arterial thrombus formation in ACS and suggest that SIRT1 may represent a novel therapeutic target in this context.
凝集素样氧化型低密度脂蛋白受体-1（LOX-1）促进内皮细胞摄取氧化型低密度脂蛋白（oxLDL），在动脉粥样硬化和急性冠状动脉综合征（ACS）中发挥重要作用。然而，其在动脉血栓形成中的作用尚不清楚。我们使用内皮细胞特异性 LOX-1 转基因小鼠（LOX-1TG）和颈动脉光化学损伤血栓形成模型，在不同 oxLDL 水平下研究 LOX-1 在体内动脉血栓形成中的作用。
在正常饮食喂养的小鼠中，与 WT 相比，LOX-1TG 小鼠的动脉闭塞时间出乎意料地延长。与此一致，LOX-1TG 小鼠颈动脉组织因子（TF）的表达和活性降低了一半。这种作用是通过激活八聚体转录因子 1（Oct-1）介导的，通过结合其启动子，上调哺乳动物去乙酰化酶沉默信息调节因子 2 相关酶 1（SIRT1），从而抑制 NF-κB 信号通路。相反，静脉注射 oxLDL 以及 6 周高胆固醇饮食导致从 Oct-1/SIRT1 信号转导途径向 ERK1/2 途径转变，从而导致血栓形成反应增强，闭塞时间缩短。
因此，LOX-1 根据 oxLDL 的激活程度，在体内不同地调节血栓形成。在低 oxLDL 水平下，LOX-1 激活保护性的 Oct-1/SIRT1 途径，而在较高水平的脂蛋白时，其转换为促血栓形成的 ERK1/2 途径。这些发现可能对 ACS 中的动脉血栓形成很重要，并表明 SIRT1 可能是该领域的一个新的治疗靶点。
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