LRP 5 deficiency down‐regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice

Abstract

Low‐density lipoprotein receptor‐related protein 5 (LRP 5) is a member of the LDLR family that orchestrates cholesterol homoeostasis. The role of LRP 5 and the canonical Wnt pathway in the vascular wall of dyslipidaemic animals remains unknown. In this study, we analysed the role of LRP 5 and the Wnt signalling pathway in mice fed a hypercholesterolaemic diet (HC) to trigger dyslipidaemia. We show that Lrp5−/− mice had larger aortic lipid infiltrations than wild‐type mice, indicating a protective role for LRP 5 in the vascular wall. Three members of the LDLR family, Lrp1, Vldlr and Lrp6, showed up‐regulated gene expression levels in aortas of Lrp5−/− mice fed a hypercholesterolaemic diet. HC feeding in Lrp5−/− mice induced higher macrophage infiltration in the aortas and accumulation of inflammatory cytokines in blood. Wnt/β‐CATENIN signalling proteins were down‐regulated in HC Lrp5−/− mice indicating that LRP 5 regulates the activation of Wnt signalling in the vascular wall. In conclusion, our findings show that LRP 5 and the canonical Wnt pathway down‐regulation regulate the dyslipidaemic profile by promoting lipid and macrophage retention in the vessel wall and increasing leucocyte‐driven systemic inflammation.