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Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors – hyperglycemia, dyslipidemia, hypertension and obesity – leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular communication. We hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction. Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs). Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs. These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS. [ABSTRACT FROM AUTHOR]

Introduction The metabolic syndrome (MetS) is characterized by the association of several disorders that increase the risk of developing cardiovascular diseases and insulin resistance. In addition to the development of type II diabetes, insulin resistance can also lead to many complications such as atherosclerosis, dyslipidemia and high blood pressure. Extracellular vesicles (EVs), including microvesicles (MVs) and exosomes can be considered as new biomarkers of different pathologies, and can be involved in intercellular communication. Aim We hypothesize that EVs could be implicated in MetS-associated insulin resistance in human endothelial cells and hepatocytes. Methods MVs and exosomes were isolated from plasma of non-MetS and MetS patients by serial centrifugation. Then, human aortic endothelial cells (HAoECs) and human hepatocytes (HepG2) were treated with EVs or palmitic acid for 24 hours, before stimulation with 100nM insulin for 5 minutes. Finally, we studied insulin signaling pathway by analyzing specific phosphorylated proteins: IRS1 at Tyr612, AKT at Ser473 and GSK3β at Ser9. Results Neither MVs nor exosomes from nMetS and MetS patients significantly modified the capacity of insulin to induce activation of AKT pathway. Also, no effect was observed when HepG2 were treated with MVs. In contrast, exosomes from MetS, but not those from nMetS patients, were able to decrease significantly the insulin-induced phosphorylation of AKT and GSK3β, in HepG2 cells without affecting IRS1 phosphorylation. Conclusion These results provide evidence: – of the specificity of the effects of exosomes regarding the hepatocytes but not the endothelial cells and; – that exosomes, but not MVs, from MetS patients may contribute to the insulin resistance in hepatocytes, by impairing the AKT- GSK3β pathway in response to insulin. [ABSTRACT FROM AUTHOR]