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Published on: May 4, 2021
Adiponectin limits monocytic microparticle-induced endothelial activation by modulation of the AMPK, Akt and NFκB
Mehroz Ehsan1, Krishna K Singh2, Fina Lovren3
1Division 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.
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.
Insights
Adiponectin limits the release and action of monocyte-derived microparticles (mono-MPs), which are linked to cardiovascular risk. This study reveals adiponectin
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Adipokine Signaling
Background:
- Monocyte-derived microparticles (mono-MPs) are implicated in linking cardiovascular risk factors to vascular injury.
- Adiponectin is known for its anti-inflammatory and vasculoprotective properties.
Purpose of the Study:
- To investigate the hypothesis that adiponectin limits the production and/or action of mono-MPs.
- To elucidate the role of adiponectin in regulating inflammatory responses mediated by mono-MPs.
Main Methods:
- Utilized flow cytometry and Western blot analyses on cell lines (THP-1), primary monocytes, and mouse models.
- Evaluated the impact of adiponectin on lipopolysaccharide (LPS)-induced mono-MP release and associated inflammatory markers.
- Assessed the effect of mono-MPs on endothelial cells (HUVECs) and the role of adiponectin in modulating these interactions.
Main Results:
- Adiponectin significantly attenuated LPS-induced mono-MP release in vitro and in vivo.
- Mice lacking adiponectin (Adipoq-/-) exhibited increased mono-MP generation compared to wild-type littermates.
- Adiponectin reduced LPS-induced inflammasome activation (NLRP3, ASC, caspase-1, IL-1β) within MPs and abrogated MP-induced VCAM-1 expression and adhesion in HUVECs.
- Mechanistically, adiponectin's effects involved the AMPK, Akt, and NFκB pathways.
Conclusions:
- Adiponectin demonstrates a novel inhibitory effect on the production and action of mono-MPs.
- These findings highlight another pleiotropic anti-inflammatory and vasculoprotective function of adiponectin.
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