期刊
DIABETES
卷 64, 期 6, 页码 2028-2041出版社
AMER DIABETES ASSOC
DOI: 10.2337/db14-1225
关键词
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资金
- Department of Science and Technology
- Department of Biotechnology
- CSIR, India, under 12th Five Year Plan project SMILE
- CSIR, India, under 12th Five Year Plan project EpiHeD
- CSIR
- Indian Council of Medical Research, New Delhi, India
Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by promoting an inflammatory environment within the vessel wall. In this study, we investigated the molecular mechanisms responsible for monocyte-to-macrophage differentiation and, subsequently, the effect of metformin in regressing angiotensin II (Ang-II)-mediated atheromatous plaque formation in ApoE(-/-) mice. AMPK activity was dose and time dependently downregulated during phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, which was accompanied by an upregulation of proinflammatory cytokine production. Of note, AMPK activators metformin and AICAR significantly attenuated PMA-induced monocyte-to-macrophage differentiation and proinflammatory cytokine production. However, inhibition of AMPK activity alone by compound C was ineffective in promoting monocyte-to-macrophage differentiation in the absence of PMA. On the other hand, inhibition of c-Jun N-terminal kinase activity inhibited PMA-induced inflammation but not differentiation, suggesting that inflammation and differentiation are independent events. In contrast, inhibition of STAT3 activity inhibited both inflammation and monocyte-to-macrophage differentiation. By decreasing STAT3 phosphorylation, metformin and AICAR through increased AMPK activation caused inhibition of monocyte-to-macrophage differentiation. Metformin attenuated Ang-II-induced atheromatous plaque formation and aortic aneurysm in ApoE(-/-) mice partly by reducing monocyte infiltration. We conclude that the AMPK-STAT3 axis plays a pivotal role in regulating monocyte-to-macrophage differentiation and that by decreasing STAT3 phosphorylation through increased AMPK activity, AMPK activators inhibit monocyte-to-macrophage differentiation.
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