Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway.
Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway.
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DOI：
10.7554/elife.58064
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发表时间：
2021-01-08
期刊：
影响因子：
7.7
通讯作者：
Feinberg MW
中科院分区：
文献类型：
--
作者：
Yang D;Haemmig S;Zhou H;Pérez-Cremades D;Sun X;Chen L;Li J;Haneo-Mejia J;Yang T;Hollan I;Feinberg MW
内皮细胞（EC）活化是慢性血管疾病发病机制的早期标志。MicroRNA-181 b（Mir 181 b）是血管内皮中重要的抗炎介质，影响内毒素血症、动脉粥样硬化和胰岛素抵抗。在此，我们确定，药物甲氨蝶呤（MTX）及其下游代谢产物腺苷发挥抗炎作用，在血管内皮细胞的靶向和激活Mir 181 b的表达。在饮食诱导的肥胖模型中，全身和内皮特异性Mir 181 a2 b2缺陷小鼠均发生血管炎症、白色脂肪组织（WAT）炎症和胰岛素抵抗。此外，MTX以Mir 181 a2 b2依赖性方式减弱饮食诱导的WAT炎症、胰岛素抵抗和EC活化。MTX通过一个独特的腺苷-腺苷受体A3-SMAD 3/4-Mir 181 b信号级联反应减弱了精氨酸诱导的EC激活。这些发现确立了内皮细胞Mir 181 b在控制血管炎症中的重要作用，并且通过高剂量MTX或腺苷信号传导恢复内皮细胞中的Mir 181 b可能为抗炎治疗提供潜在的治疗机会。
Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b (Mir181b) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating Mir181b expression. Both systemic and endothelial-specific Mir181a2b2-deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a Mir181a2b2-dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4-Mir181b signaling cascade. These findings establish an essential role of endothelial Mir181b in controlling vascular inflammation and that restoring Mir181b in ECs by high-dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.