| First Author | Zhang M | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 19 | Pages | 7888-7903 |
| PubMed ID | 28330873 | Mgi Jnum | J:242770 |
| Mgi Id | MGI:5906511 | Doi | 10.1074/jbc.M117.779447 |
| Citation | Zhang M, et al. (2017) AMP-activated protein kinase alpha1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation. J Biol Chem 292(19):7888-7903 |
| abstractText | 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 alpha1 (AMPKalpha1) 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 AMPKalpha1 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-/-/AMPKalpha1-/- 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-/-/AMPKalpha1-/- bone marrow and in myeloid-specific AMPKalpha1-deficient ApoE-/- mice. Finally, rapamycin treatment, which abolished delayed monocyte differentiation in ApoE-/-/AMPKalpha1-/- mice, lost its atherosclerosis-lowering effects in these mice. Mechanistically, we found that AMPKalpha1 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 AMPKalpha1-/- mice. Our results reveal that AMPKalpha1 deficiency impairs autophagy-mediated monocyte differentiation and decreases monocyte/macrophage survival, which attenuates atherosclerosis in ApoE-/- mice in vivo. |
