Adiponectin limits monocytic microparticle-induced endothelial activation by modulation of the AMPK, Akt and NFκB signaling pathways

Mehroz Ehsan; Krishna K Singh; Fina Lovren; Yi Pan; Adrian Quan; Laura-Eve Mantella; Paul Sandhu; Hwee Teoh; Mohammed Al-Omran; Subodh Verma

doi:10.1016/j.atherosclerosis.2015.11.024

Adiponectin limits monocytic microparticle-induced endothelial activation by modulation of the AMPK, Akt and NFκB signaling pathways

Atherosclerosis. 2016 Feb:245:1-11. doi: 10.1016/j.atherosclerosis.2015.11.024. Epub 2015 Nov 25.

Authors

Mehroz Ehsan¹, Krishna K Singh², Fina Lovren³, Yi Pan⁴, Adrian Quan⁵, Laura-Eve Mantella⁶, Paul Sandhu⁷, Hwee Teoh⁸, Mohammed Al-Omran⁹, Subodh Verma¹⁰

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.

PMID: 26687997
DOI: 10.1016/j.atherosclerosis.2015.11.024

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.

Conclusion: Adiponectin exerts novel effects to limit the production and action of mono-MPs, underscoring yet another pleiotropic effect of this adipokine.

Keywords: AMPK; Adiponectin; Endothelial cell; Microparticles; Monocyte; NFκB.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / biosynthesis
AMP-Activated Protein Kinases / genetics*
Adiponectin / biosynthesis
Adiponectin / genetics*
Animals
Atherosclerosis / genetics*
Atherosclerosis / metabolism
Atherosclerosis / pathology
Blotting, Western
Cells, Cultured
Disease Models, Animal
Endothelial Cells / metabolism
Endothelial Cells / ultrastructure
Endothelium, Vascular / metabolism
Endothelium, Vascular / ultrastructure
Gene Expression Regulation*
Humans
Inflammasomes / metabolism
Male
Mice
Mice, Inbred C57BL
Microscopy, Electron, Transmission
Monocytes / metabolism
Monocytes / ultrastructure
NF-kappa B / biosynthesis
NF-kappa B / genetics*
Proto-Oncogene Proteins c-akt / biosynthesis
Proto-Oncogene Proteins c-akt / genetics*
RNA / genetics*
Real-Time Polymerase Chain Reaction
Risk Factors
Signal Transduction

Substances

Adiponectin
Inflammasomes
NF-kappa B
RNA
Proto-Oncogene Proteins c-akt
AMP-Activated Protein Kinases