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

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 () mice, which show impaired clearing of plasma lipoproteins and spontaneously develop atherosclerosis, /α mice showed reduced sizes of atherosclerotic lesions and lesser numbers of macrophages in the lesions. Furthermore, aortic lesions were decreased in mice transplanted with/α bone marrow and in myeloid-specific AMPKα1-deficient mice. Finally, rapamycin treatment, which abolished delayed monocyte differentiation in/α 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 α mice. Our results reveal that AMPKα1 deficiency impairs autophagy-mediated monocyte differentiation and decreases monocyte/macrophage survival, which attenuates atherosclerosis in mice.

Pyruvate kinase M knockdown–induced signaling via AMP-activated protein kinase promotes mitochondrial biogenesis, autophagy, and cancer cell survival

“…Our observation of induction of autophagy in H1299 stable cells for PKM1 and PKM2 knockdown is consistent with a recent study by Zhang et al (35), wherein it was shown that AMPK regulated the expression of key autophagic marker ULK1 and LC3B in a FoxO3 (transcription factor)-dependent manner. It is well-known that AMPK directly stimulates autophagy by phosphorylating Ulk1 at Ser-317 and Ser-777 residues (36).…”

AMP-activated protein kinase: the current landscape for drug development

“…AMPK suppression of macrophage inflammation within plaques 228,230,251 and adipose tissue 219 may also be important for suppressing atherosclerosis development. In addition to regulating macrophage polarization, increased proliferation of monocytes to macrophages and reductions in autophagy are important for atherosclerosis 252 , and in this regard, AMPK inhibition of cellular proliferative pathways such as mTOR and p53 as well as the induction of autophagy would be expected to reduce atherosclerosis progression 253 ; however, this has not been observed in all studies 254 . Similarly, the induction of autophagy may reduce atherosclerosis and improve plaque stability, further supporting the possible beneficial role of activating macrophage AMPK 255 .…”

AMPKα1 is essential for Glucocorticoid Receptor triggered anti-inflammatory macrophage activation

“…FOXO3 is an indirect GR target through the activation of SGK1 that alleviates the inhibition of Foxo3 transcriptional activity, which is synergized with the activation of FOXO3 transcriptional activity by AMPK. FOXO3 was shown to be required for the differentiation of monocytes into macrophages via activation of AMPKa1 and autophagy (Zhang et al, 2017b) and to promote anti-viral response in macrophages (Zhang et al, 2019b). Strikingly, FOXO3 is involved in the GC-driven anti-inflammatory response in Systemic Lupus Erythematosus through the reinforcement of the blockage of NF-KB activity (Lu et al, 2016).…”