Reduction of AMP-Activated Protein Kinase alpha 2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo

Title
Reduction of AMP-Activated Protein Kinase alpha 2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo
Author(s)
최형철동윤조[동윤조]장미아오[장미아오]리앙빈[리앙빈]시종린[시종린]자오젱싱[자오젱싱]아스파시마[아스파시마]조밍휘[조밍휘]
Keywords
VEIN ENDOTHELIAL-CELLS; NITRIC-OXIDE SYNTHASE; ACCELERATED ATHEROSCLEROSIS; GLUCOSE-HOMEOSTASIS; TYROSINE NITRATION; S-GLUTATHIOLATION; INDUCED APOPTOSIS; DEFICIENT MICE; UP-REGULATION; MOUSE MODEL
Issue Date
201002
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Citation
CIRCULATION, v.121, no.6, pp.792 - 803
Abstract
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 Ca(2+). 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 Ca(2+) homeostasis. (Circulation. 2010; 121: 792-803.)
URI
http://hdl.handle.net/YU.REPOSITORY/22916http://dx.doi.org/10.1161/CIRCULATIONAHA.109.900928
ISSN
0009-7322
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의과대학 > 약리학교실 > Articles
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