title: LRP5 deficiency down-regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice.
abstract: Low-density lipoprotein receptor-related protein 5 (LRP5) is a member of the LDLR family that orchestrates cholesterol homoeostasis. The role of LRP5 and the canonical Wnt pathway in the vascular wall of dyslipidaemic animals remains unknown. In this study, we analysed the role of LRP5 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 LRP5 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 LRP5 regulates the activation of Wnt signalling in the vascular wall. In conclusion, our findings show that LRP5 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.
authors: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors: Maria
authors: M
authors: Borrell-Pagès
authors: July Carolina
authors: JC
authors: Romero
authors: Lina
authors: L
authors: Badimon
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation; D050171:Dyslipidemias / Q000097:blood / Q000209:etiology / Q000235:genetics*; D015870:Gene Expression; D006937:Hypercholesterolemia / Q000097:blood / Q000209:etiology / Q000235:genetics; D007150:Immunohistochemistry; D008055:Lipids / Q000032:analysis* / Q000097:blood; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000172:deficiency / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002791:Cholesterol, Dietary; D008055:Lipids; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C486645:Lrp1 protein, mouse; C055127:Lrp2 protein, mouse; C555483:Lrp5 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D051176:beta Catenin
keywords: LRP5; atherosclerosis; canonical Wnt signalling; macrophages; plasma cholesterol
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