Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages

• Published in: European heart journal Vol. 32; no. 22; pp. 2841 - 2850
• Main Authors: Borrell-Pagès, Maria, Romero, July Carolina, Juan-Babot, Oriol, Badimon, Lina
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2011
• Subjects: Apoptosis - physiology; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Bone Morphogenetic Protein 2 - metabolism; Cardiology. Vascular system; Cell Differentiation - physiology; Cell Movement - physiology; Cell Survival - physiology; Cells, Cultured; Foam Cells - physiology; Humans; Lipid Metabolism - physiology; Lipoproteins, LDL - pharmacology; Low Density Lipoprotein Receptor-Related Protein-5 - antagonists & inhibitors; Low Density Lipoprotein Receptor-Related Protein-5 - metabolism; Low Density Lipoprotein Receptor-Related Protein-5 - physiology; Macrophages - metabolism; Medical sciences; Monocytes - metabolism; Osteopontin - metabolism; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Wnt Signaling Pathway - physiology; LRP5; Wnt signalling; Lipid uptake; Atherosclerosis; Human macrophages; Human; Migration; Cardiovascular disease; Lipids; Activation; Lipoprotein; Density; Uptake; Vascular disease; Regulation(control); Low; Receptor protein; Circulatory system; Cardiology; Cell; Macrophage
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehr062

Aims Atherosclerosis plaque development includes infiltration of inflammatory cells, accumulation of lipids and fibrous cap formation. Low-density lipoprotein receptor-related protein 1 (LRP1) is expressed on atherosclerotic lesions associated with macrophages and vascular smooth muscle cells. The aim of this work is to analyse the role in atherosclerosis lesion progression of another member of the LDL receptor protein family, low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor with Frizzled known to activate the Wnt signalling pathway in several cell types. Methods and results LRP5 is expressed in human vascular and innate inflammatory cells. LRP5 is transcriptionally regulated by aggregated LDL (agLDL), participating in the lipid uptake and transformation of macrophages into foam cells, a critical step in atherosclerosis progression. AgLDL-treated macrophages show up-regulated expression of β-catenin, LEF1, c-jun, cyclinD1, bone morphogenetic protein 2 (BMP2), and osteopontin (OPN), proteins and targets of the Wnt signalling pathway, whereas LRP5-silenced macrophages show a significant down-regulation of OPN and BMP2 expression. Furthermore, LRP5-deficient macrophages exhibit an impaired migration both in wound-repair and modified Boyden chambers models. Conclusion These results demonstrate the involvement of LRP5 in the innate inflammatory reaction to lipid infiltration in atherosclerosis.