A MP-activated protein kinase (AMPK) is a serine/threonine kinase consisting of ␣, ␤, and ␥ subunits, each of which has at least 2 isoforms. The ␣ subunit possesses catalytic activity, whereas the ␤ and ␥ regulatory subunits maintain the stability of the heterotrimer complex. AMPK phosphorylates multiple targets, in vivo and in vitro. These targets include several biosynthetic enzymes such as acetylCoA carboxylase, hydroxymethylglutaryl-CoA reductase, and glycogen synthase. The importance of AMPK␣ is illustrated by the fact that dual deficiency of AMPK␣1 and -␣2, the 2 catalytic subunits of AMPK, is embryonic lethal. 1 The major isoform of AMPK in endothelial cells is Original

Background-Aberrant endoplasmic reticulum (ER) stress is associated with several cardiovascular diseases, including atherosclerosis. The mechanism by which aberrant ER stress develops is poorly understood. This study investigated whether dysfunction of AMP-activated protein kinase (AMPK) causes aberrant ER stress and atherosclerosis in vivo. Methods and Results-Human umbilical vein endothelial cells and mouse aortic endothelial cells from AMPK-deficient mice were used to assess the level of ER stress with Western blotting. Reduction of AMPK␣2 expression significantly increased the level of ER stress in human umbilical vein endothelial cells. In addition, mouse aortic endothelial cells from AMPK␣2 knockout (AMPK␣2