TY - JOUR TI - Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway AU - Yang, Dafeng AU - Haemmig, Stefan AU - Zhou, Haoyang AU - PĂ©rez-Cremades, Daniel AU - Sun, Xinghui AU - Chen, Lei AU - Li, Jie AU - Haneo-Mejia, Jorge AU - Yang, Tianlun AU - Hollan, Ivana AU - Feinberg, Mark W A2 - Tontonoz, Peter A2 - Barton, Matthias VL - 10 PY - 2021 DA - 2021/01/08 SP - e58064 C1 - eLife 2021;10:e58064 DO - 10.7554/eLife.58064 UR - https://doi.org/10.7554/eLife.58064 AB - 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. KW - endothelial cells KW - microRNA KW - inflammation KW - adenosine KW - methotrexate JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -