(VP111) THE DIRECT AMPK-β1 SELECTIVE ACTIVATOR PF-06409577 TARGETS MACROPHAGES TO REDUCE ATHEROSCLEROSIS IN MICE

Background: 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. AMPK inhibits cholesterol synthesis and inflammation; however, the importance of therapeutic targeting is not known as to date only compounds that indirectly activate the kinase and have multiple other molecular targets and metabolic effects (i.e. metformin, canagliflozin, salsalate) or have low oral and cellular bioavailability (i.e. A769662) have been examined.

METHODS AND RESULTS: In the current study we have tested the effects of an orally bioavailable and potent activator of AMPK, PF-06409577, that selectively targets AMPKβ1 containing complexes which are predominately expressed in the liver and immune cells including macrophages. We find that daily oral gavage of ApoE null mice or PCSK9 over-expressing mice with PF-06409577 reduced the development of atherosclerotic plaques through a mechanism dependent on the AMPK β1 isoform. This reduction in atherosclerosis was not associated with changes in hepatic or plasma lipids levels but instead was associated with reductions in inflammation. In cultured bone marrow derived macrophages PF-06409577 robustly activates macrophage AMPK, and reduced macrophage cholesterol and triglyceride synthesis while increasing cholesterol efflux, effects requiring the AMPKβ1 isoform.

Conclusion: Pharmacologically targeting macrophage AMPK β1 reduces inflammation and atherosclerosis in two murine models and therefore may be a promising strategy to treat atherosclerosis.