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.

Wnt signaling in cardiovascular disease: opportunities and challenges

“…Badimon’s group demonstrated that LRP5 inhibits aortic macrophage infiltration and inflammatory cytokine production in mice fed diets that induce hypercholesterolemia [66]. The mechanism is not completely understood, but may relate to LRP5-dependent promotion of an anti-inflammatory macrophage phenotype [67].…”

Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease

“…17 This effect was surprising since Wnt signaling in the vascular smooth muscle cell (VSMC) is implicated in stimulating osteoblastic transition and vascular calcification. 35, 36 However, recent studies demonstrate that inhibition of Wnt signaling stimulates lipid accumulation in atherosclerotic plaques, 37 and that Dkk1 mediated inhibition of aortic Wnt7b stimulates smad mediated aortic endothelial-mesenchymal transition (EndMT) and vascular calcification. 38 EndMT is a developmental physiologic process involved in the development of the cardiac valves, the cardiac septum and the aortic root, 39, 40 and it may 41 or may not 42 contribute to cardiac fibrosis in various adult disease states.…”

Macrophages of genetically characterized familial hypercholesterolaemia patients show up‐regulation of LDL‐receptor‐related proteins

“…The contribution of LRP5 to cholesterol metabolism was previously suggested by the observation that ApoE −/− LRP5 −/− mice have larger atherosclerotic lesions than their ApoE −/− littermates 74. Beyond its role in promoting lipid internalization, increased expression of LRP5 also induces the activation of canonical Wnt signalling 22, 31. In macrophages, canonical Wnt signalling is thought to promote cell motility through a β‐catenin‐dependent mechanism 75.…”

“…Our group has shown that LRP5 is involved in monocyte differentiation into macrophage [30] and is up-regulated in macrophages exposed to agLDL [22]. In vivo analyses in Lrp5 À/À mice fed a hypercholesterolaemic (HC) diet showed that LRP5 deficiency increases the development of aortic atherosclerotic lesions, suggesting an atheroprotective role for LRP5 [31,32]. LRP5 belongs to the LDL receptor superfamily and shares common motifs including LDLR type A repeats, EGF-like domains and transmembrane anchors.…”