Activation of the AMP-activated protein kinase (AMPK) in vascular cells has been linked to anti- inflammatory effects some of which have been attributed to the phosphorylation of the endothelial nitric oxide synthase (eNOS). However, we and others have been unable to detect an acute effect of AMPK on eNOS. A constitutively active mutant of the AMPK did however increase eNOS expression via activation of MEF2A and KLF2. Instead of AMPK activating eNOS we found that NO activates the AMPK which results in the phosphorylation and inhibition of the HMG CoA reductase as well as that of FoxO1A. Both of the latter have anti-inflammatory consequences as inhibition of the HMG CoA reductase attenuates Ras and ERK signaling while the inhibition of FoxO1A reduces angiopoietin 2 expression. AMPK activation also affects NFkB activity and results in a significant decrease in the TNF-a- induced phosphorylation of the p65 subunit as well as the inhibition of IkB phosphorylation. The latter is reflected in endothelial cells from AMPKa2^-/- mice as the IL-1b-induced expression of E- selectin and VCAM-1 was significantly increased. Taken together, these results indicate that the anti-inflammatory effects associated with AMPK activation can be at least partially attributed to an increase of eNOS expression in endothelial cells as well as to effects on the activity of at least 4 transcription factors; FoxO1A, MEF2A, KLF-2 and NFkB.