Activation of AMP-Activated Protein Kinase Inhibits Oxidized LDL-Triggered Endoplasmic Reticulum Stress In Vivo

作者：Dong Yunzhou; Zhang Miao; Wang Shuangxi; Liang Bin; Zhao Zhengxing; Liu Chao; Wu Mingyuan; Choi Hyoung Chul; Lyons Timothy J; Zou Ming Hui^*

来源：Diabetes, 2010, 59(6): 1386-1396.

DOI：10.2337/db09-1637

OBJECTIVE-The oxidation of LDLs is considered a key step in the development of atherosclerosis. How LDL oxidation contributes to atherosclerosis remains poorly defined. Here we report that oxidized and glycated LDL (HOG-LDL) causes aberrant endoplasmic reticulum (ER) stress and that the AMP-activated protein kinase (AMPK) suppressed HOG-LDL-triggered ER stress in vivo.
RESEARCH DESIGN AND METHODS-ER stress markers, sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity and oxidation, and AMPK activity were monitored in cultured bovine aortic endothelial cells (BAECs) exposed to HOG-LDL or in isolated aortae from mice fed an atherogenic diet.
RESULTS-Exposure of BAECs to clinically relevant concentrations of HOG-LDL induced prolonged ER stress and reduced SERCA activity but increased SERCA oxidation. Chronic administration of Tempol (a potent antioxidant) attenuated both SERCA oxidation and aberrant ER stress in mice fed a high-fat diet in vivo. Likewise, AMPK activation by pharmacological (5'-aminoimidazole-4-carboxymide-1-beta-n-ribofuranoside, metformin, and statin) or genetic means (adenoviral overexpression of constitutively active AMPK mutants) significantly mitigated ER stress and SERCA oxidation and improved the endothelium-dependent relaxation in isolated mouse aortae. Finally, Tempol administration markedly attenuated impaired endothelium-dependent vasorelaxation, SERCA oxidation, ER stress, and atherosclerosis in ApoE(-/-) and ApoE(-/-)/AMPK alpha 2(-/-) fed a high-fat diet.
CONCLUSION-We conclude that HOG-LDL, via enhanced SERCA oxidation, causes aberrant ER stress, endothelial dysfunction, and atherosclerosis in vivo, all of which are inhibited by AMPK activation. Diabetes 59:1386-1396, 2010

• 出版日期2010-6