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Inflammatory adipocyte-derived extracellular vesicles promote leukocyte attachment to vascular endothelial cells

Wadey, Rebecca M., Connolly, Katherine D., Mathew, Donna, Walters, Gareth, Rees, D. Aled and James, Philip E. 2019. Inflammatory adipocyte-derived extracellular vesicles promote leukocyte attachment to vascular endothelial cells. Atherosclerosis 283 , pp. 19-27. 10.1016/j.atherosclerosis.2019.01.013
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Abstract

Background and aims Obesity is associated with an increased risk of cardiovascular disease, but the mechanisms involved are not completely understood. In obesity, the adipocyte microenvironment is characterised by both hypoxia and inflammation. Therefore, we sought to determine whether extracellular vesicles (EVs) derived from adipocytes in this setting might be involved in mediating cardiovascular disease, specifically by promoting leukocyte attachment to vascular endothelial cells. Methods Mature 3T3-L1 adipocytes were incubated for 24 h under control, TNF-α (30 ng/mL), hypoxia (1% O2), or TNF-α+hypoxia (30 ng/mL, 1% O2) conditions. EVs were isolated by differential ultracentrifugation and analysed by nanoparticle tracking analysis. Primary human umbilical vein endothelial cells (HUVECs) were treated with EVs for 6 h before being lysed for Western blotting to investigate changes in adhesion molecule production, or for use in leukocyte attachment assays. Results EVs from adipocytes treated with TNF-α and TNF-α+hypoxia increased vascular cell adhesion molecule (VCAM-1) production in HUVECs compared to basal level (4.2 ± 0.6 and 3.8 ± 0.3-fold increase, respectively (p < 0.05)), an effect that was inhibited by an anti-TNF-α neutralising antibody. Production of other adhesion molecules (E-selectin, P-selectin, platelet endothelial cell adhesion molecule and VE-Cadherin) was unchanged. Pre-incubating HUVECs with TNF-α+hypoxia EVs significantly increased leukocyte attachment compared to basal level (3.0 ± 0.4-fold increase (p < 0.05)). Conclusions Inflammatory adipocyte EVs induce VCAM-1 production in vascular endothelial cells, accompanied by enhanced leukocyte attachment. Preventing adipocyte derived EV-induced VCAM-1 upregulation may offer a novel therapeutic target in the prevention of obesity-driven cardiovascular disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0021-9150
Date of First Compliant Deposit: 24 January 2019
Date of Acceptance: 10 January 2019
Last Modified: 28 Jun 2019 10:46
URI: http://orca-mwe.cf.ac.uk/id/eprint/118822

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