AMPK activation reduces the number of atheromata macrophages in ApoE deficient mice

CC chemokine receptor 2 (Ccr2) governs migration of inflammatory Ly6C^hi monocytes from the bone marrow (BM) to the circulating blood, which is a key step for macrophage accumulation during progression of atherosclerosis. Hyperlipidemia is often accompanied by low AMP-activated kinase (AMPK) activity and increased expression of Ccr2. The aim of this study was to examine whether there is a link between AMPK and chemokine networks.

ApoE^-/- mice were fed a western diet and treated daily with AMPK activators (AICAR, A769662, or Metformin) or vehicle for 10 weeks. The effect of AMPK activators on pro-inflammatory myeloid cell numbers within the BM, blood, spleen, and aorta of ApoE^-/- mice was then examined.

We found that AMPK activation significantly reduced the number of Ly6C^hi monocytes in the blood and atherosclerotic plaques. This reduction was caused by down-regulation of Ccr2 protein expression, which inhibited Ccr2-mediated migration of Ly6C^hi monocytes from the BM to the circulation. There was no effect on proliferation or apoptosis of BM-derived Ly6C^hi monocytes. AMPK activation caused Ly6C^hi monocytes to accumulate in the BM, with a concomitant reduction in numbers in the blood and spleen.

AMPK activation reduces the formation of atheromata-inducing macrophages in ApoE^-/--deficient mice by inhibiting expression of Ccr2, thereby preventing the Ccr2-mediated migration of Ly6C^hi monocytes from the BM. Therefore, AMPK may be a promising target for the treatment of atherosclerosis.