Inflammatory adipocyte-derived extracellular vesicles promote leukocyte attachment to vascular endothelial cells
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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.
Wadey, R.M., Connolly, K.D., Mathew, D., Walters, G., Rees, D.A. and James, P.E. (2019) 'Inflammatory adipocyte-derived extracellular vesicles promote leukocyte attachment to vascular endothelial cells', Atherosclerosis, 283, p.19-27. DOI: 10.1016/j.atherosclerosis.2019.01.013.
Dynodwr Gwrthrych Digidol (DOI)https://doi.org/10.1016/j.atherosclerosis.2019.01.013
Article published in Atherosclerosis on 24 January 2019 (online), available at: https://doi.org/10.1016/j.atherosclerosis.2019.01.013.
Cardiff Metropolitan University (Grant ID: Cardiff Metropolian (Internal))
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Connolly, Katherine; Wadey, Rebecca; Matthew, Donna; Johnson, Errin; Rees, D. Aled; James, Philip (Oxford University Press, 2018-07-16)Adipocyte-derived extracellular vesicles (EVs) may serve as novel endocrine mediators of adipose tissue and impact upon vascular health. However, it is unclear whether adipocyte-derived EVs are present in the human ...
Bariatric surgery is accompanied by changes in extracellular vesicle-associated and plasma Fatty Acid Binding Protein 4 Witczak, Justyna; Min, Thinzar; Prior, Sarah L.; Stephens, Jeffrey W.; James, Philip; Rees, Aled (Springer link, 2017-08-19)BACKGROUND: Bariatric surgery markedly reduces fat mass with beneficial effects on cardiometabolic health but the mechanisms involved are not fully understood. Extracellular vesicles (EVs) are secreted by a variety of ...
Nitrite-derived nitric oxide reduces hypoxia-inducible factor 1α-mediated extracellular vesicle production by endothelial cells Burnley-Hall, Nicholas; Willis, Gareth; Davis, Jessica; Rees, D. Aled; James, Philip (Elsevier, 2016-12-23)Introduction Extracellular vesicles (EVs) are small, spherical particles enclosed by a phospholipid bilayer (∼30–1000 nm) released from multiple cell types, and have been shown to have pathophysiological roles in a ...