Hydroxytyrosol and its main plasma circulating metabolites attenuate the initial steps of atherosclerosis through inhibition of the MAPK pathway

The main aim of this work is to gain insight into the potential mechanisms of hydroxytyrosol (HT) and its mainplasmatic 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 ex-pression compared with the control group in the isolated aorta. Furtherin-vitromechanistic assays revealed thatboth HT and HTmet could reduce the adhesion of Jurkat-T-lymphocytes to human aortic endothelial cells at1–5 μM, significantly greater reductions being observed with HTmet. This process appeared to be regulated bythe MAPK pathway through the inactivation of p38δ, JNK1-3, CREB, AKT3, p53 and P70 S6 Kinase. We con-cluded that supplementation with HT precursors from olive oil might attenuate the initial steps of atherosclerosisat a molecular level. The reduction of lymphocyte adhesion and the modulation of MAPK pathway by HTmetcould explain this phenomenon.This work was partly supported by state grant: The MEFOPC Project (Subprojects AGL2012-40144-C03-02 and AGL2012-40144-C03-03) from the Spanish Ministry of Education and Science (Ministerio de Educación y Ciencia). We wish to acknowledge the support of the Institut d’Investigació Sanitària Pere Virgili (IISPV) and the EURECAT-Centre Tecnològic de Nutrició i Salut (CTNS), Reus, Spain and the University of Lleida through the M-C. López de las Hazas grant and the L. Rubió Sara Borrell postdoctoral grant (CD14/00275). And the Ú. Catalán Pla estratègic de recerca i innovació en salut (PERIS) post-doctoral grant (SLT002/16/00239; Catalunya, Spain). NFOC-Salut group is a consolidated research group of Generalitat de Catalunya, Spain (2014 SGR 873)