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J Biol Chem. 2017 May 12;292(19):7888-7903. doi: 10.1074/jbc.M117.779447. Epub 2017 Mar 22.

AMP-activated protein kinase α1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation.

Author information

1
From the Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104 and.
2
the Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia 30302-5035.
3
the Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia 30302-5035 mzou@gsu.edu.

Abstract

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 in ApoE-/- mice transplanted with ApoE-/-/AMPKα1-/- bone marrow and in myeloid-specific AMPKα1-deficient ApoE-/- mice. Finally, rapamycin treatment, which abolished delayed monocyte differentiation in ApoE-/-/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 from AMPKα1-/- mice. Our results reveal that AMPKα1 deficiency impairs autophagy-mediated monocyte differentiation and decreases monocyte/macrophage survival, which attenuates atherosclerosis in ApoE-/- mice in vivo.

KEYWORDS:

AMP-activated kinase (AMPK); atherosclerosis; autophagy; macrophage; monocyte; monocytes

PMID:
28330873
PMCID:
PMC5427268
DOI:
10.1074/jbc.M117.779447
[Indexed for MEDLINE]
Free PMC Article

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