Department of Cardiovascular Surgery, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou 451464, China.
Chem Res Toxicol. 2020 Apr 20;33(4):975-981. doi: 10.1021/acs.chemrestox.9b00509. Epub 2020 Mar 23.
Oxidized low-density lipoprotein (ox-LDL)- induced endothelial insults plays an important role in the pathogenesis of atherosclerosis. Donepezil is a well-known acetylcholinesterase inhibitor with its primary application being the treatment of Alzheimer's disease. More recently, there has been increased interest in donepezil as an antiatherosclerosis treatment as it possesses a host of relevant and potentially beneficial properties. In the present study, we found that donepezil could reduce the expression of lectin-type oxidized low-density lipoprotein receptor-1 (LOX-1) in human aortic endothelial cells (HAECs). We found that donepezil could suppress the expression of intercellular adhesion molecule-1 (ICAM-1), which recruits monocytes to adhere to the endothelium, by more than half. Another key finding of our study is that donepezil could reduce the expression of tumor necrosis factor receptor-α (TNF-α) and interleukin-6 (IL-6) by more than half at both the mRNA and protein transcriptional levels. Donepezil also reduced the expression of tissue factor (TF), which is considerably upregulated in atherosclerotic lesions, by more than half. Finally, we turned our attention to the early growth response protein-1 (Egr-1) for its potential role in mediating the effects of donepezil. Through our Egr-1 overexpression experiment, we found that overexpression of Egr-1 almost completely abolished the effects of donepezil described above. Thus, the effects of donepezil are likely mediated through downregulation of Egr-1. These findings provide evidence that donepezil may exert protective effects against atherosclerosis.
氧化型低密度脂蛋白（ox-LDL）诱导的内皮损伤在动脉粥样硬化的发病机制中起重要作用。多奈哌齐是一种众所周知的乙酰胆碱酯酶抑制剂，主要用于治疗阿尔茨海默病。最近，人们对多奈哌齐作为一种抗动脉粥样硬化治疗药物越来越感兴趣，因为它具有许多相关的潜在有益特性。在本研究中，我们发现多奈哌齐可以降低人主动脉内皮细胞（HAECs）中凝集素型氧化型低密度脂蛋白受体-1（LOX-1）的表达。我们发现多奈哌齐可以抑制细胞间黏附分子-1（ICAM-1）的表达，ICAM-1 可使单核细胞募集并黏附在内皮细胞上，其抑制率超过一半。我们研究的另一个重要发现是，多奈哌齐可以使肿瘤坏死因子受体-α（TNF-α）和白细胞介素-6（IL-6）的表达在转录水平上降低超过一半，无论是在 mRNA 还是蛋白质水平上。多奈哌齐还使组织因子（TF）的表达降低超过一半，TF 在动脉粥样硬化病变中显著上调。最后，我们将注意力转向早期生长反应蛋白-1（Egr-1），因为它可能在介导多奈哌齐的作用中发挥作用。通过我们的 Egr-1 过表达实验，我们发现 Egr-1 的过表达几乎完全消除了上述多奈哌齐的作用。因此，多奈哌齐的作用可能是通过下调 Egr-1 介导的。这些发现为多奈哌齐可能对动脉粥样硬化发挥保护作用提供了证据。
