AMP-activated protein kinase α1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation.
Monocyte-to-macrophage differentiation, which can be initiated by physiological or atherogenic factors, is a pivotal process in atherogenesis, a disorder in which monocytes adhere to endothelial cells and subsequently migrate into the subendothelial spaces, where they differentiate into macrophages and macrophage-derived foam cells and cause atherosclerotic lesions. However, the monocyte-differentiation signaling pathways that are activated by atherogenic factors are poorly defined. Here we report that the AMP-activated protein kinase α1 (AMPKα1) in monocytes promotes atherosclerosis by increasing monocyte differentiation and survival. Exposure of monocytes to oxidized low-density lipoprotein, 7-ketocholesterol, phorbol 12-myristate 13-acetate, or macrophage colony-stimulated factor (M-CSF) significantly activated AMPK and promoted monocyte-to-macrophage differentiation. M-CSF-activated AMPK is via M-CSF receptor-dependent reactive oxygen species production. Consistently, genetic deletion of AMPKα1 or pharmacological inhibition of AMPK blunted monocyte-to-macrophage differentiation and promoted monocyte/macrophage apoptosis. Compared with apolipoprotein E knock-out (ApoE-/-) mice, which show impaired clearing of plasma lipoproteins and spontaneously develop atherosclerosis,ApoE-/-/AMPKα1-/-mice showed reduced sizes of atherosclerotic lesions and lesser numbers of macrophages in the lesions. Furthermore, aortic lesions were decreased inApoE-/-mice transplanted withApoE-/-/AMPKα1-/-bone marrow and in myeloid-specific AMPKα1-deficientApoE-/-mice. Finally, rapamycin treatment, which abolished delayed monocyte differentiation inApoE-/-/AMPKα1-/-mice, lost its atherosclerosis-lowering effects in these mice. Mechanistically, we found that AMPKα1 regulates FoxO3-dependent expression of both LC3 and ULK1, which are two important autophagy-related markers. Rapamycin treatment increased FoxO3 activity as well as LC3 and ULK1 expressions in macrophages fromAMPKα1-/-mice. Our results reveal that AMPKα1 deficiency impairs autophagy-mediated monocyte differentiation and decreases monocyte/macrophage survival, which attenuates atherosclerosis inApoE-/-micein vivo.
From the Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104 and.
Miao
M
Zhang
the Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia 30302-5035.
Huaiping
H
Zhu
the Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia 30302-5035.
Ye
Y
Ding
the Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia 30302-5035.
Zhaoyu
Z
Liu
the Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia 30302-5035.
Zhejun
Z
Cai
the Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia 30302-5035 mzou@gsu.edu.
Ming-Hui
MH
Zou
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005434:Flow Cytometry; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000737:chemistry
D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D016173:Macrophage Colony-Stimulating Factor; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D020123:Sirolimus
AMP-activated kinase (AMPK); atherosclerosis; autophagy; macrophage; monocyte; monocytes