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The main aim of this work is to gain insight into the potential mechanisms of hydroxytyrosol (HT) and its main plasmatic metabolites (HTmet) that improve the endothelial function. Feeding ApoE−/− mice with 10 mg/kg/day of HT derivatives for 12 weeks significantly reduced E-selectin, VCAM-1, MCP-1, ICAM-1, and F4/80 expression compared with the control group in the isolated aorta. Further in-vitro mechanistic assays revealed that both HT and HTmet could reduce the adhesion of Jurkat-T-lymphocytes to human aortic endothelial cells at 1–5 µM, significantly greater reductions being observed with HTmet. This process appeared to be regulated by the MAPK pathway through the inactivation of p38δ, JNK1-3, CREB, AKT3, p53 and P70 S6 Kinase. We concluded that supplementation with HT precursors from olive oil might attenuate the initial steps of atherosclerosis at a molecular level. The reduction of lymphocyte adhesion and the modulation of MAPK pathway by HTmet could explain this phenomenon.