Activation of AMP-Activated Protein Kinase Inhibits Oxidized LDL-Triggered Endoplasmic Reticulum Stress In Vivo
- Yunzhou Dong1,
- Miao Zhang1,
- Shuangxi Wang1,
- Bin Liang1,
- Zhengxing Zhao1,
- Chao Liu1,
- Mingyuan Wu1,
- Hyoung Chul Choi2,
- Timothy J. Lyons1 and
- Ming-Hui Zou1
- 1Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and
- 2Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Korea.
- Corresponding author: Ming-Hui Zou, ming-hui-zou{at}ouhsc.edu.
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Y.D. and M.Z. contributed equally to this study.
Abstract
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-β-d-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−/−/AMPKα2−/− 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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Received November 7, 2009.
- Accepted February 24, 2010.
- © 2010 by the American Diabetes Association.
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