However, current thinking suggests that reduced AMPK activity predisposes to endothelial dysfunction, while AMPK activation by laminar shear stress may contribute to vasculoprotection.20 Thus, our finding that MTX activates AMPK in human ECs may provide an important mechanistic explanation for the clinical observation of reduced CVD in patients with RA, prescribed this drug. This evidence concerns the gene PRKAA2 and endothelial dysfunction.