title: Adiponectin limits monocytic microparticle-induced endothelial activation by modulation of the AMPK, Akt and NFκB signaling pathways.
abstract: OBJECTIVE
  Monocyte-derived microparticles (mono-MPs) are emerging as critical transducers of inflammatory signals, and have been suggested to link cardiovascular risk factors to vascular injury. Since adiponectin has been proposed to exert multiple anti-inflammatory and vasculoprotective effects, we hypothesized that it might serve to limit the production and/or action of mono-MPs.
  
  
  METHODS
  Flow cytometry and western blot studies were conducted on THP-1 cells, THP-1-derived MPs, human umbilical vein endothelial cells (HUVECs), peripheral blood CD14+ monocytes and mice to evaluate the effects of adiponectin on mono-MPs.
  
  
  RESULTS
  Adiponectin attenuated lipopolysaccharide (LPS)-evoked MP release from THP-1 monocytes (30% difference) and peripheral blood monocytes (both P < 0.05) as well as dampened LPS-induced mono-MP generation in vivo. Furthermore, peritoneal monocytes from Adipoq(-/-) mice generated significantly greater MPs than those from Adipoq(+/+) littermates in the absence (2.3 fold difference, P < 0.05) and presence (1.6 fold difference, P < 0.05) of LPS. LPS-induced MP expression of NLRP3 inflammasome and its key components, namely cleaved ASC, caspase-1 and IL-1β (pro- and cleaved), were markedly attenuated by adiponectin. HUVECs incubated with MPs from LPS-treated THP-1 cells exhibited increased VCAM-1 levels and adhesion to THP-1 cells. Adiponectin abrogated these effects. From a mechanistic standpoint, the effects of adiponectin on MP release and molecular signaling occurred at least in part through the AMPK, Akt and NFκB pathways.
  
  
  CONCLUSIONS
  Adiponectin exerts novel effects to limit the production and action of mono-MPs, underscoring yet another pleiotropic effect of this adipokine.
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada. Electronic address: ehsanm@smh.ca.
authors.forename: Mehroz
authors.initials: M
authors.lastname: Ehsan
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Division of Vascular Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada. Electronic address: singhk@smh.ca.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. Electronic address: lovren@smh.ca.
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. Electronic address: pany@smh.ca.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. Electronic address: quana@smh.ca.
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada. Electronic address: MantellaLa@smh.ca.
authors.forename: Laura-Eve
authors.initials: LE
authors.lastname: Mantella
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. Electronic address: paul.singh.sandhu@gmail.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Sandhu
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Division of Endocrinology & Metabolism, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. Electronic address: teohh@smh.ca.
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.affiliation: Division of Vascular Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada. Electronic address: alomranm@smh.ca.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada. Electronic address: vermasu@smh.ca.
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D052242:Adiponectin / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009000:Monocytes / Q000378:metabolism / Q000648:ultrastructure; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D052242:Adiponectin; D058847:Inflammasomes; D016328:NF-kappa B; D012313:RNA; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Adiponectin; Endothelial cell; Microparticles; Monocyte; NFκB