A Peptide Analogue of Selectin Ligands Attenuated Atherosclerosis by Inhibiting Monocyte Activation
A Peptide Analogue of Selectin Ligands Attenuated Atherosclerosis by Inhibiting Monocyte Activation
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选择素配体的肽类似物通过抑制单核细胞活化减轻动脉粥样硬化
DOI：
10.1155/2019/8709583
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发表时间：
2019-05
影响因子：
4.6
通讯作者：
Huang Rongchong
中科院分区：
文献类型：
--
作者：
Ye Zhishuai;Zhang Shanfeng;Liu Yubo;Wang Shujing;Zhang Jianing;Huang Rongchong
背景：循环单核细胞在动脉粥样硬化的发病机制中起着重要作用。单核细胞归巢到动脉粥样硬化的部位主要是由选择素启动的。因此，阻断选择素及其配体的相互作用在单核细胞归巢中具有重要作用，这可能是一种潜在的治疗动脉粥样硬化的方法。在这里，我们研究了一种新型的选择素配体IELLQAR多肽类似物在动脉粥样硬化中的疗效。方法与结果首次用流式细胞仪检测了IELLQAR选择素结合肽对P-、E-和L-选择素与单核细胞结合的抑制作用，发现其对P-选择素与单核细胞结合的抑制作用呈剂量依赖性，特别是对P-选择素与人外周血单核细胞结合的抑制作用(IC50~5μM)和THP-1细胞(IC50~10μM)。此外，IELLQAR还可抑制P-选择素诱导的单核细胞表面CD11b的活化，减少单核细胞与内皮细胞的黏附。ApoE−/−小鼠给予或不给予IELLQAR(1或3 mg/kg)喂养西式饮食，或采用部分左颈动脉结扎诱导动脉粥样硬化。在白三烯和磷脂酰胆碱诱导的动脉粥样硬化模型中，用IELLQAR多肽治疗的载脂蛋白E−/−小鼠动脉粥样硬化斑块形成和动脉壁单核/巨噬细胞浸润均减少。我们的结果还表明，IELLQAR通过P-选择素依赖的核因子(NF-)κB和哺乳动物雷帕霉素靶标(MTOR)通路的激活来抑制单核细胞向巨噬细胞的分化。结论IELLQAR是一种选择素配体的多肽类似物，它能抑制选择素与单核细胞的结合，从而通过抑制单核细胞的活化而减轻动脉粥样硬化。因此，IELLQAR多肽的使用为疾病早期动脉粥样硬化的治疗提供了一种新的方法，并代表了一种有前途的候选药物。
Background Circulating monocytes play a critical role in the pathogenesis of atherosclerosis. Monocyte homing to sites of atherosclerosis is primarily initiated by selectin. Thus, blockade of the interaction of selectins and their ligands holds a significant role in monocyte homing which might be a potential approach to treat atherosclerosis. Here, we investigated the efficacy of a novel peptide analogue of selectin ligands IELLQAR in atherosclerosis. Methods and Results In this study, we firstly measured the effect of the IELLQAR selectin-binding peptide on the inhibition of binding of selectins to monocytes by flow cytometry, which exhibited a dose-dependent inhibitory effect on the binding of the P-, E-, and L-selectins to monocytes, especially the inhibition of P-selectin binding to human peripheral blood monocytes (PBMCs) (half maximal inhibitory concentration (IC50~5 μM)) and THP-1 cells (IC50~10 μM). Furthermore, IELLQAR inhibited P-selectin-induced activation of CD11b on the surface of monocytes and decreased adhesion of monocytes to the endothelium. ApoE−/− mice with or without IELLQAR (1 or 3 mg/kg) fed a Western-type diet (WTD) or which had disturbed blood flow-induced shear stress underwent partial left carotid artery ligation (PLCA) to induce atherosclerosis. In the WTD- and PLCA-induced atherosclerosis models, atherosclerotic plaque formation and monocyte/macrophage infiltration of the arterial wall both decreased in ApoE−/− mice treated with the IELLQAR peptide. Our results also revealed that IELLQAR inhibited the differentiation of monocytes into macrophages through P-selectin-dependent activation of the nuclear factor- (NF-) κB and mammalian target of rapamycin (mTOR) pathways. Conclusion Collectively, our results demonstrated that IELLQAR, a peptide analogue of selectin ligands, inhibited selectin binding to monocytes, which led to subsequent attenuation of atherosclerosis via inhibition of monocyte activation. Hence, use of the IELLQAR peptide provides a new approach and represents a promising candidate for the treatment of atherosclerosis in the early stage of disease.
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DOI：
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期刊：
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DOI：
10.1136/bmj.323.7325.1375/a
发表时间：
2001-12
期刊：
BMJ : British Medical Journal
影响因子：
--
作者：
K. Barraclough
通讯作者：
K. Barraclough
影响因子：
6.7
作者：
Gremmel, Thomas;Koppensteiner, Renate;Panzer, Simon
通讯作者：
Panzer, Simon
DOI：
10.1017/cbo9781139207249.009
发表时间：
2012
期刊：
--
影响因子：
--
作者：
W. Marsden
通讯作者：
W. Marsden
DOI：
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发表时间：
2005
期刊：
Journal of Jilin University
影响因子：
--
作者：
L. Qing
通讯作者：
L. Qing