Kidder Evan, Pea Meleah, Cheng Siyuan, Koppada Satya-Priya, Visvanathan Suren, Henderson Quartina, Thuzar Moe, Yu Xiuping, Alfaidi Mabruka
Department of Internal Medicine-Division of Cardiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, United States.
Department of Urology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, United States.
Front Cardiovasc Med. 2023 Jul 19;10:1190460. doi: 10.3389/fcvm.2023.1190460. eCollection 2023.
Atherosclerosis is a progressive disease that develops in areas of disturbed flow (d-flow). Progressive atherosclerosis is characterized by bulky plaques rich in mesenchymal cells and high-grade inflammation that can rupture leading to sudden cardiac death or acute myocardial infarction. In response to d-flow, endothelial cells acquire a mesenchymal phenotype through endothelial-to-mesenchymal transition (EndMT). However, the signaling intermediaries that link d-flow to EndMT are incompletely understood.
In this study we found that in human atherosclerosis, cells expressing SNAI1 (Snail 1, EndMT transcription factor) were highly expressed within the endothelial cell (EC) layer and in the pre-necrotic areas in unstable lesions, whereas stable lesions did not show any SNAI1 positive cells, suggesting a role for EndMT in lesion instability. The interleukin-1 (IL-1), which signals through the type-I IL-1 receptor (IL-1R1), has been implicated in plaque instability and linked to EndMT formation . Interestingly, we observed an association between SNAI1 and IL-1R1 within ECs in the unstable lesions. To establish the causal relationship between EndMT and IL-1R1 expression, we next examined IL-1R1 levels in our endothelial-specific lineage tracing mice. IL-1R1 and Snail1 were highly expressed in ECs under atheroprone compared to athero-protective areas, and oscillatory shear stress (OSS) increased IL-1R1 protein and mRNA levels . Exposure of ECs to OSS resulted in loss of their EC markers and higher induction of EndMT markers. By contrast, genetic silencing of IL-1R1 significantly reduced the expression of EndMT markers and Snail1 nuclear translocation, suggesting a direct role for IL-1R1 in d-flow-induced EndMT. , re-analysis of scRNA-seq datasets in carotid artery exposed to d-flow confirmed the IL-1R1 upregulation among EndMT population, and in our partial carotid ligation model of d-flow, endothelial cell specific IL-1R1 KO significantly reduced SNAI1 expression.
Global inhibition of IL-1 signaling in atherosclerosis as a therapeutic target has recently been tested in the completed CANTOS trial, with promising results. However, the data on IL-1R1 signaling in different vascular cell-types are inconsistent. Herein, we show endothelial IL-1R1 as a novel mechanosensitive receptor that couples d-flow to IL-1 signaling in EndMT.
动脉粥样硬化是一种在血流紊乱区域（d-flow）发展的进行性疾病。进行性动脉粥样硬化的特征是富含间充质细胞和高度炎症的大块斑块，这些斑块可能破裂，导致心源性猝死或急性心肌梗死。作为对d-flow的反应，内皮细胞通过内皮-间充质转化（EndMT）获得间充质表型。然而，将d-flow与EndMT联系起来的信号中介尚不完全清楚。
在本研究中，我们发现，在人类动脉粥样硬化中，表达SNAI1（Snail 1，EndMT转录因子）的细胞在内皮细胞（EC）层和不稳定病变的坏死前区域高度表达，而稳定病变中未显示任何SNAI1阳性细胞，这表明EndMT在病变不稳定中起作用。通过I型白细胞介素-1受体（IL-1R1）发出信号的白细胞介素-1（IL-1）与斑块不稳定有关，并与EndMT形成相关。有趣的是，我们在不稳定病变的EC内观察到SNAI1与IL-1R1之间存在关联。为了确定EndMT与IL-1R1表达之间的因果关系，我们接下来在我们的内皮特异性谱系追踪小鼠中检测了IL-1R1水平。与抗动脉粥样硬化区域相比，在易患动脉粥样硬化区域的EC中，IL-1R1和Snail1高度表达，并且振荡剪切应力（OSS）增加了IL-1R1蛋白和mRNA水平。将EC暴露于OSS导致其EC标志物丢失，并更高地诱导EndMT标志物。相比之下，IL-1R1的基因沉默显著降低了EndMT标志物的表达和Snail1核转位，表明IL-1R1在d-flow诱导的EndMT中起直接作用。对暴露于d-flow的颈动脉的scRNA-seq数据集的重新分析证实了EndMT群体中IL-1R1的上调，并且在我们的d-flow部分颈动脉结扎模型中，内皮细胞特异性IL-1R1基因敲除显著降低了SNAI1的表达。
最近在完成的CANTOS试验中测试了将动脉粥样硬化中IL-1信号的整体抑制作为治疗靶点，结果令人鼓舞。然而，关于不同血管细胞类型中IL-1R1信号的数据并不一致。在此，我们表明内皮IL-1R1是一种新型的机械敏感受体，它将d-flow与EndMT中的IL-1信号联系起来。
