Reduction of AMP-Activated Protein Kinase α2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo

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 alpha 2 expression significantly increased the level of ER stress in human umbilical vein endothelial cells. In addition, mouse aortic endothelial cells from AMPK alpha 2 knockout (AMPK alpha 2(-/-)) mice had higher expression of markers of ER stress and increased levels of intracellular Ca2+. These phenotypes were abolished by adenovirally overexpressing constitutively active AMPK mutants (Ad-AMPK-CA) or by transfecting sarcoendoplasmic reticulum calcium ATPase (SERCA). Inhibition of SERCA induced ER stress in endothelial cells. Furthermore, reduction of AMPK alpha expression suppressed SERCA activity. In addition, SERCA activity was significantly reduced concomitantly with increased oxidation of SERCA in mouse aortic endothelial cells from AMPK alpha 2(-/-) mice. Both of these phenotypes were abolished by adenovirally overexpressing Ad-AMPK-CA. Furthermore, Tempol, which restored SERCA activity and decreased oxidized SERCA levels, markedly reduced the level of ER stress in mouse aortic endothelial cells from AMPK alpha 2(-/-) mice. Finally, oral administration of tauroursodeoxycholic acid, a chemical chaperone that inhibits ER stress, significantly reduced both ER stress and aortic lesion development in low-density lipoprotein receptor-and AMPK alpha 2-deficient mice. Conclusion-These results suggest that AMPK functions as a physiological suppressor of ER stress by maintaining SERCA activity and intracellular Ca2+ homeostasis. (Circulation. 2010; 121: 792-803.)