Macrophages of genetically characterized familial hypercholesterolaemia patients show up-regulation of LDL-receptor-related proteins.
Familial hypercholesterolaemia (FH) is a major risk for premature coronary heart disease due to severe long-life exposure to high LDL levels. Accumulation of LDL in the vascular wall triggers atherosclerosis with activation of the innate immunity system. Here, we have investigated (i) gene expression of LDLR and LRPs in peripheral blood cells (PBLs) and in differentiated macrophages of young FH-patients; and (ii) whether macrophage from FH patients have a differential response when exposed to high levels of atherogenic LDL. PBLs in young heterozygous genetically characterized FH patients have higher expression of LRP5 and LRP6 than age-matched healthy controls or patients with secondary hypercholesterolaemia. LRP1 levels were similar among groups. In monocyte-derived macrophages (MACs), LRP5 and LRP1 transcript levels did not differ between FHs and controls in resting conditions, but when exposed to agLDL, FH-MAC showed a highly significant up-regulation of LRP5, while LRP1 was unaffected. PBL and MAC cells from FH patients had significantly lower LDLR expression than control cells, independently of the lipid-lowering therapy. Furthermore, exposure of FH-MAC to agLDL resulted in a reduced expression of CD163, scavenger receptor with anti-inflammatory and atheroprotective properties. In summary, our results show for first time that LRPs, active lipid-internalizing receptors, are up-regulated in innate immunity cells of young FH patients that have functional LDLR mutations. Additionally, their reduced CD163 expression indicates less atheroprotection. Both mechanisms may play a synergic effect on the onset of premature atherosclerosis in FH patients.
Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
Rafael
R
Escate
Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
Teresa
T
Padro
Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
Maria
M
Borrell-Pages
Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
Rosa
R
Suades
Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
Rosa
R
Aledo
Foundation Jimenez Diaz, Madrid, Spain.
Pedro
P
Mata
Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.|Cardiovascular Research Chair, UAB, Barcelona, Spain.
Lina
L
Badimon
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D008078:Cholesterol, LDL; D026502:LDL-Receptor Related Proteins; C475476:LRP1 protein, human; C555482:LRP5 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011956:Receptors, Cell Surface; D011973:Receptors, LDL
CD163; LRPs; atherosclerosis; familial hypercholesterolaemia; macrophages
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