Abstract
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.
Highlights
Activated endothelial cells (ECs) orchestrate the expression of adhesion molecules and release chemokines to foster the recruitment of leukocytes into the vessel wall
MTX attenuates TNF-a-induced EC activation by upregulation of MIR181B-2 expression. Because of their known anti-inflammatory effects in the vascular endothelium (Diamantis et al, 2017; Mangoni et al, 2017), we explored whether MTX or HMG-CoA reductase inhibitors activated the expression of the anti-inflammatory MIR181B (Lin et al, 2016; Sun et al, 2014a; MICU Registry et al, 2012; Sun et al, 2016)
We found that SMAD2 and SMAD3 expression decreased in MTX-treated iEC-knockout mice (KO) mice compared to flox-Cre mice, whereas there were no differences between flox-Cre and iEC-KO mice without MTX treatment, suggesting a feedback mechanism involved in the MTX-SMAD-Mir181b cascade (Figure 5—figure supplement 3)
Summary
Activated endothelial cells (ECs) orchestrate the expression of adhesion molecules and release chemokines to foster the recruitment of leukocytes into the vessel wall. Accumulating studies demonstrate that targeting EC activation and/or dysfunction may open new therapeutic approaches for the prevention and treatment of inflammatory diseases (Chen et al, 2017; Gareus et al, 2008; Nus et al, 2016). Inhibition of NF-kB activity in the vascular endothelium significantly reduced atherosclerotic plaque formation and progression (Gareus et al, 2008)
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