Targeting AMP Kinase in Myeloid Cells to Reduce Atherosclerosis

Abstract

Subjects with diabetes have a 1.8 times greater risk of having a heart attack than subjects without diabetes. Although cardiovascular mortality has decreased by 30.8% in the last decade, it is still responsible for 1 in 3 deaths in the U.S. (1). In spite of targeting the common risk factors, there is still a residual burden for atherosclerotic cardiovascular disease (ASCVD) (2). As inflammatory processes are involved in every stage of atherosclerosis, targeting inflammation has become an attractive strategy for further reducing the incidence of ASCVD (3).AMP activated kinase (AMPK) is an enzyme that increases cellular ATP generation and diminishes ATP use for less critical processes (4). It regulates the transport of glucose, the synthesis of lipids and proteins, and the rate of fuel metabolism. It is also involved in regulating inflammation and oxidative and ER stress (5). AMPK may thus provide the link between nutrient, metabolic, and inflammatory stimuli. Dysregulation of AMPK may therefore play a role in the pathogenesis of diabetes, hypertension, and ASCVD. On the basis of the information cited above, activation of AMPK could prevent or treat these conditions.Although there is evidence that AMPK activation is atheroprotective, the specific mechanism responsible for this effect is unclear (6). To explore the hypothesis that the atheroprotective effect of AMPK is due to the suppression of macrophage inflammation, Cao et al. (7) have investigated whether myeloid deletion of a1AMPK exacerbates atherosclerosis and whether this is associated with an increase in macrophage inflammation and chemotaxis and an alteration in cholesterol and lipid metabolism. To investigate this hypothesis they created a myeloid a1AMPK knockout (MAKO) in the LDL receptor knockout (LDLRKO) mice (MAKO/LDLRKO). Control floxed/ LDLRKO and MAKO/LDLRKO mice were fed an atherogenic diet for 16 weeks, and various analyses were done to quantify atherosclerosis, macrophage inflammation, chemotaxis, lipid and cholesterol metabolism, and liver inflammation. a1AMPK mRNA and protein were decreased specifically in bone marrow-derived macrophages (BMDMs) and peritoneal macrophages in the MAKO/LDLRKO mice. The MAKO/LDLRKO mice were similar in weight and insulin sensitivity but had higher total and LDL cholesterol than controls. Atherosclerotic lesions were increased by 38 and 63% in the aortic roots and whole aorta, respectively, in the MAKO/LDLRKO mice. Deletion of a1AMPK increased basal and lipopolysaccharidestimulated proinflammatory genes and macrophage adhesion to endothelial cells in BMDMs isolated from MAKO/LDLRKO mice. The macrophage content in atherosclerotic plaque was increased in the MAKO/LDLRKO mice along with an increase in chemotactic chemokines. Inflammatory genes were also upregulated in macrophages isolated from the atherosclerotic plaques of MAKO/LDLRKO mice. The higher cholesterol levels in MAKO/LDLRKO mice were associated with an increase in apolipoprotein B (apoB100 and apoB48) in plasma and in apoB mRNA and protein and expression...