Macrophage AMPK ß1 activation by PF-06409577 reduces the inflammatory response, cholesterol synthesis, and atherosclerosis in mice

Abstract: Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the developed world and is characterized by both chronic low-grade inflammation and dyslipidemia. AMP-activated protein kinase (AMPK) inhibits cholesterol synthesis and dampens inflammation. While activation of AMPK has been shown to have beneficial effects on aspects of atherosclerosis, to date, only compounds that indirectly and non-specifically activate the kinase (i.e. metformin, canagliflozin, salsalate) or have low oral and cellular bioavailability (i.e. A769662) have been examined. In the current study, we have tested the effects of an orally bioavailable and potent activator of AMPK, PF-06409577, that selectively targets AMPKb1-containing complexes which are predominately expressed in the murine liver and immune cells, including macrophages. We found that daily oral gavage with PF-06409577 reduced levels of atherosclerotic plaque in two models of atherosclerosis through a mechanism dependent on the AMPKb1 isoform in myeloid cells. These observations were not associated with changes in hepatic or plasma lipid levels but instead was associated with reductions in inflammatory pathways in macrophages. In cultured bone marrow-derived macrophages, PF-06409577 activated AMPK and reduced inflammatory pathways including the NF-?B pathway as well as fatty acid and cholesterol synthesis; effects requiring the AMPKß1 isoform. These data indicate that pharmacologically targeting macrophage AMPKß1 may be a promising strategy for reducing atherosclerosis. Overall design: Murine Bone Marrow derived Macrophages from Wildtype and AMPKbeta1 knockout mice were treated with 10uM PF-06409577 or Veh (DMSO) for 6 hours to assess the effects of AMPK activation on inflammation and metabolism.