Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice

CXCR4型 趋化因子受体 趋化因子 趋化因子受体 癌症研究 细胞生物学 生物 受体 血管平滑肌 细胞 免疫学 炎症 内分泌学 生物化学 平滑肌
作者
İsmail Çimen,Lucia Natarelli,Zahra Abedi Kichi,James M. Henderson,Floriana Maria Farina,Eva Briem,Maria Aslani,Remco T. A. Megens,Yvonne Jansen,Elizabeth Mann-Fallenbuchel,Selin Gencer,Johan Duchêne,Maliheh Nazari-Jahantigh,Emiel P. C. van der Vorst,Wolfgang Enard,Yvonne Döring,Andreas Schober,Donato Santovito,Christian Weber
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:15 (720) 被引量:1
标识
DOI:10.1126/scitranslmed.adf3357
摘要

The CXC chemokine receptor 4 (CXCR4) in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is crucial for vascular integrity. The atheroprotective functions of CXCR4 in vascular cells may be counteracted by atherogenic functions in other nonvascular cell types. Thus, strategies for cell-specifically augmenting CXCR4 function in vascular cells are crucial if this receptor is to be useful as a therapeutic target in treating atherosclerosis and other vascular disorders. Here, we identified miR-206-3p as a vascular-specific CXCR4 repressor and exploited a target-site blocker (CXCR4-TSB) that disrupted the interaction of miR-206-3p with CXCR4 in vitro and in vivo. In vitro, CXCR4-TSB enhanced CXCR4 expression in human and murine ECs and VSMCs to modulate cell viability, proliferation, and migration. Systemic administration of CXCR4-TSB in Apoe -deficient mice enhanced Cxcr4 expression in ECs and VSMCs in the walls of blood vessels, reduced vascular permeability and monocyte adhesion to endothelium, and attenuated the development of diet-induced atherosclerosis. CXCR4-TSB also increased CXCR4 expression in B cells, corroborating its atheroprotective role in this cell type. Analyses of human atherosclerotic plaque specimens revealed a decrease in CXCR4 and an increase in miR-206-3p expression in advanced compared with early lesions, supporting a role for the miR-206-3p–CXCR4 interaction in human disease. Disrupting the miR-206-3p–CXCR4 interaction in a cell-specific manner with target-site blockers is a potential therapeutic approach that could be used to treat atherosclerosis and other vascular diseases.
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