TY - JOUR
T1 - Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages
AU - Borrell-Pags, Maria
AU - Romero, July Carolina
AU - Juan-Babot, Oriol
AU - Badimon, Lina
N1 - Funding Information:
This work was supported by the Spanish Ministry of Science (SAF2006-10091 to L.B.), Instituto de Salud CarlosIII (CIBEROBN-CB06/03 to L.B.), and RyC (RyC2007-01466 to M.B.-P.).
PY - 2011/11
Y1 - 2011/11
N2 - 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 resultsLRP5 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. ConclusionThese results demonstrate the involvement of LRP5 in the innate inflammatory reaction to lipid infiltration in atherosclerosis.
AB - 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 resultsLRP5 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. ConclusionThese results demonstrate the involvement of LRP5 in the innate inflammatory reaction to lipid infiltration in atherosclerosis.
KW - Atherosclerosis
KW - Human macrophages
KW - LRP5
KW - Lipid uptake
KW - Wnt signalling
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U2 - 10.1093/eurheartj/ehr062
DO - 10.1093/eurheartj/ehr062
M3 - Article
C2 - 21398644
AN - SCOPUS:80052782624
SN - 0195-668X
VL - 32
SP - 2841
EP - 2850
JO - European heart journal
JF - European heart journal
IS - 22
ER -