title: Ezetimibe inhibits PMA-induced monocyte/macrophage differentiation by altering microRNA expression: a novel anti-atherosclerotic mechanism.
abstract: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol both in monotherapy or combined with a statin. However, its effect on atherosclerosis plaque progression is certainly unknown. MicroRNAs are short non-encoding RNA molecules dynamically implicated in monocytic differentiation which is considered an essential process during atherosclerosis development. The purpose of this study was to investigate the effect of ezetimibe on monocyte/macrophage differentiation as well as the implication of microRNAs (miRNAs) in this process. THP-1 differentiation with PMA became cells adherent to the plastic surface, and induced the expression of macrophage surface markers (CD11a, CD11b and ICAM-1) and miR-155, miR-222, miR-424 and miR-503. In the presence of ezetimibe, the adhesive capacity of THP-1 cells was decreased in a dose-dependent manner (P<0.05) and the expression of CD11a, CD11b and ICAM-1 was almost totally inhibited (P<0.05). The expression of miR-155, miR-222, miR-424 and miR-503 was reduced by 55%, 100%, 75% and 100%, respectively (P<0.05). Further mechanistic studies demonstrated that ezetimibe suppressed the PMA-induced phosphorylation of ERK/MAPK and inhibited the NF-κB activity, which are upstream signalling molecules in the differentiation process. In conclusion, ezetimibe inhibits PMA-induced THP-1 cell differentiation into macrophage-like cells in association with the inhibition of miRNA pathways. Our study suggests that inhibition of miRNAs might form a novel mechanism of anti-atherosclerotic effect of ezetimibe.
authors.affiliation: Laboratorio de Biología Vascular, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Sótano norte (Medicina Nuclear), C/ Martín Lagos s/n, 28040 Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Muñoz-Pacheco
authors.forename: Adriana
authors.initials: A
authors.lastname: Ortega-Hernández
authors.forename: María
authors.initials: M
authors.lastname: Miana
authors.forename: Victoria
authors.initials: V
authors.lastname: Cachofeiro
authors.forename: Arturo
authors.initials: A
authors.lastname: Fernández-Cruz
authors.forename: Dulcenombre
authors.initials: D
authors.lastname: Gómez-Garre
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000517:prevention & control*; D001384:Azetidines / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D000069438:Ezetimibe; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D035683:MicroRNAs; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C016658:phorbolol myristate acetate; D000069438:Ezetimibe; D013755:Tetradecanoylphorbol Acetate