Abstract
BackgroundAtherosclerosis preferentially develops in regions of disturbed flow (DF). Emerging evidence indicates that yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway, sense different blood flow patterns and regulate atherosclerotic lesions. We previously found that methotrexate (MTX) reduces in-stent neoatherosclerosis, decreases the plaque burden, and has an effect on local fluid shear stress. Here, we investigated the atheroprotective effect of MTX under DF and the mechanisms underlying these properties.MethodsHuman umbilical vein endothelial cells (HUVECs) were subjected to biomechanical stretch using a parallel-plate flow system and treated with or without MTX at therapeutically relevant concentrations. Additionally, an extravascular device was used to induce DF in the left common carotid artery of C57BL/6 mice, followed by treatment with MTX or 0.9% saline. The artery was then assessed histopathologically after 4 weeks on a Western diet.ResultsWe observed that MTX significantly inhibited DF-induced endothelial YAP/TAZ activation. Furthermore, it markedly decreased pro-inflammatory factor secretion and monocyte adhesion in HUVECs but had no effect on apoptosis. Mechanistically, AMPKa1 depletion attenuated these effects of MTX. Accordingly, MTX decreased DF-induced plaque formation, which was accompanied by YAP/TAZ downregulation in vivo.ConclusionsTaken together, we conclude that MTX exerts protective effects via the AMP-dependent kinase (AMPK)-YAP/TAZ pathway. These results provide a basis for the prevention and treatment of atherosclerosis via the inhibition of YAP/TAZ.
Highlights
Atherosclerosis preferentially develops in regions of disturbed flow (DF)
Haemodynamic regulation of the activation and nuclear localisation of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) in Human umbilical vein endothelial cells (HUVECs) To investigate the roles of YAP/TAZ in HUVECs under different shear forces, cultured HUVECs were exposed to unidirectional shear stress (USS), DF, or STA for 10 h
Our results demonstrated that DF leads to a significant decrease in p-YAP (Ser127) (Fig. 1a, b) and marked increases in ICAM1, VCAM1, and TAZ expression (Fig. 1a)
Summary
Atherosclerosis preferentially develops in regions of disturbed flow (DF). Emerging evidence indicates that yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway, sense different blood flow patterns and regulate atherosclerotic lesions. We previously found that methotrexate (MTX) reduces in-stent neoatherosclerosis, decreases the plaque burden, and has an effect on local fluid shear stress. Several studies have demonstrated that long-term lowdose methotrexate (MTX) therapy in rheumatoid arthritis is associated with reduced cardiovascular disease and cardiovascular mortality [9, 10]. AMPK plays a role in promoting YAP phosphorylation at Ser127, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation; AMPK activation results in YAP phosphorylation and inactivation [14,15,16]. We hypothesised that the AMPK pathway mediates YAP/TAZ functional inactivation and the atheroprotective effects of MTX
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