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Signal Transduction

Metformin Inhibits Monocyte-to-Macrophage Differentiation via AMPK-Mediated Inhibition of STAT3 Activation: Potential Role in Atherosclerosis

  1. Sathish Babu Vasamsetti1,
  2. Santosh Karnewar1,
  3. Anantha Koteswararao Kanugula1,
  4. Avinash Raj Thatipalli2,
  5. Jerald Mahesh Kumar2⇑ and
  6. Srigiridhar Kotamraju1⇑
  1. 1Centre for Chemical Biology, Council of Scientific and Industrial Research (CSIR)–Indian Institute of Chemical Technology, Hyderabad, India
  2. 2CSIR–Centre for Cellular and Molecular Biology, Hyderabad, India
  1. Corresponding authors: Srigiridhar Kotamraju, giridhar{at}iict.res.in, and Jerald M. Kumar, mahesh73{at}ccmb.res.in.
Diabetes 2015 Jun; 64(6): 2028-2041. https://doi.org/10.2337/db14-1225
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Abstract

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.

Footnotes

  • See accompanying article, p. 1907.

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-1225/-/DC1.

  • Received August 7, 2014.
  • Accepted December 20, 2014.
  • © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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Metformin Inhibits Monocyte-to-Macrophage Differentiation via AMPK-Mediated Inhibition of STAT3 Activation: Potential Role in Atherosclerosis
Sathish Babu Vasamsetti, Santosh Karnewar, Anantha Koteswararao Kanugula, Avinash Raj Thatipalli, Jerald Mahesh Kumar, Srigiridhar Kotamraju
Diabetes Jun 2015, 64 (6) 2028-2041; DOI: 10.2337/db14-1225

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Metformin Inhibits Monocyte-to-Macrophage Differentiation via AMPK-Mediated Inhibition of STAT3 Activation: Potential Role in Atherosclerosis
Sathish Babu Vasamsetti, Santosh Karnewar, Anantha Koteswararao Kanugula, Avinash Raj Thatipalli, Jerald Mahesh Kumar, Srigiridhar Kotamraju
Diabetes Jun 2015, 64 (6) 2028-2041; DOI: 10.2337/db14-1225
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