title: Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis.
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.
authors.affiliation: Centre for Chemical Biology, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Sathish Babu
authors.initials: SB
authors.lastname: Vasamsetti
authors.affiliation: Centre for Chemical Biology, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Karnewar
authors.affiliation: Centre for Chemical Biology, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Anantha Koteswararao
authors.initials: AK
authors.lastname: Kanugula
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Avinash Raj
authors.initials: AR
authors.lastname: Thatipalli
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India giridhar@iict.res.in mahesh73@ccmb.res.in.
authors.forename: Jerald Mahesh
authors.initials: JM
authors.lastname: Kumar
authors.affiliation: Centre for Chemical Biology, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Technology, Hyderabad, India giridhar@iict.res.in mahesh73@ccmb.res.in.
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects*; D011109:Polymethacrylic Acids / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D011109:Polymethacrylic Acids; D050796:STAT3 Transcription Factor; D008687:Metformin; D055372:AMP-Activated Protein Kinases