LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4

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