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Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium
Basic Research in Cardiology ( IF 9.5 ) Pub Date : 2022-06-08 , DOI: 10.1007/s00395-022-00937-4
Selin Gencer 1 , Yvonne Döring 1, 2, 3 , Yvonne Jansen 1 , Soyolmaa Bayasgalan 1 , Yi Yan 1, 2 , Mariaelvy Bianchini 1 , Ismail Cimen 1 , Madeleine Müller 1 , Linsey J F Peters 1, 4, 5 , Remco T A Megens 1, 2, 6 , Philipp von Hundelshausen 1, 2 , Johan Duchene 1 , Patricia Lemnitzer 1 , Oliver Soehnlein 1, 7, 8 , Christian Weber 1, 2, 6, 9 , Emiel P C van der Vorst 1, 2, 4, 5
Affiliation  

Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12–CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe−/− mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3’s role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways.



中文翻译:

内皮 ACKR3 通过促进免疫细胞粘附到血管内皮来驱动动脉粥样硬化

动脉粥样硬化是潜在致命心血管疾病的基础,其特征是在大动脉中形成斑块。当前旨在减少动脉粥样硬化危险因素的治疗方法仍然为较大的残余风险留有余地;因此,需要针对炎症的新型治疗候选药物。内皮是动脉粥样硬化血管炎症的起点,我们之前可以证明趋化因子轴 CXCL12–CXCR4 在疾病发展中起着重要作用。然而,ACKR3(CXCL12 的替代和更高亲和力受体)的作用仍有待阐明。我们使用缺乏Ackr3的西方饮食喂养的Apoe -/-小鼠研究了动脉 ACKR3 在动脉粥样硬化中的作用在动脉内皮细胞和平滑肌细胞中。我们首次表明,由于动脉粘附减少和免疫细胞入侵,ACKR3 的动脉内皮缺陷会减轻动脉粥样硬化。发炎的人冠状动脉内皮细胞中的 ACKR3 沉默降低了粘附分子的表达,从而初步验证了 ACKR3 在内皮粘附中的作用。同时,ACKR3 沉默下调了 MAPK 通路中的关键介质,例如 ERK1/2,以及 NF-kB p65 亚基的磷酸化。动脉粥样硬化病变中的内皮细胞也显示 ACKR3 缺陷小鼠中磷酸化 NF-kB p65 表达降低。缺乏平滑肌细胞特异性以及造血细胞 ACKR3 不会影响小鼠的动脉粥样硬化。总的来说,

更新日期:2022-06-09
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