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 alpha 1 (AMPK alpha 1) 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-tomacrophage differentiation. M-CSF-activated AMPK is via M-CSFreceptor-dependent reactive oxygen species production. Consistently, genetic deletion of AMPK alpha 1 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(-/-) / AMPKK alpha 1(-/-) 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(-/-) / AMPKK alpha 1(-/-) bone marrow and in myeloid-specific AMPKK alpha 1deficient ApoE(-/-) mice. Finally, rapamycin treatment, which abolished delayed monocyte differentiation in ApoE(-/-) / AMPKK alpha 1(-/-) mice, lost its atherosclerosis-lowering effects in these mice. Mechanistically, we found that AMPKK alpha 1 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 AMPKK alpha 1(-/-) mice. Our results reveal that AMPKK alpha 1 deficiency impairs autophagy-mediated monocyte differentiation and decreases monocyte/ macrophage survival, which attenuates atherosclerosis in ApoE(-/-) mice in vivo.