Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis.
BACKGROUND
There is clinical interest in identifying novel lipid biomarkers for evaluating cardiovascular risk and targeting lipid-lowering treatment. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in the dysregulated cholesterol transfer from modified lipoproteins to human coronary vascular smooth muscle cells (hVSMCs), promoting hVSMC-derived foam cell formation. LRP1 has a soluble and circulating form (sLRP1) generated from LRP1. Cholesterol modulates the release of the soluble form of LRP1. Using in vitro, ex vivo and patient-based approaches, we tested the association between circulating sLRP1 concentrations and hypercholesterolemia and the potential of sLRP1 as a biomarker of atherosclerosis.


RESULTS
Circulating sLRP1 concentrations were higher in severe hypercholesterolemia compared to moderate hypercholesterolemia or normocholesterolemia (Study 1). Circulating sLRP1 was significantly associated with established pro-atherogenic lipid parameters in two different hypercholesterolemic populations (Studies 2 and 3). sLRP1 concentrations decreased after statin treatment and increased after statin withdrawal (Study 3). In vitro experiments showed that native LDL, aggregated LDL and VLDL+IDL lipoproteins induced the release of sLRP1 from hVSMC. sLRP1 levels were increased in the conditioned medium of coronary atherosclerotic plaque areas extracted from patients compared to non-atherosclerotic areas of the same coronary artery and patient. Circulating sLRP1 concentrations were independently associated with the occurrence of carotid atherosclerosis in a hypercholesterolemic population (Study 2). The later association was higher than that observed for other classical or novel lipid parameters.


CONCLUSIONS
Circulating sLRP1 is a new lipid-related parameter potentially useful as a biomarker for atherosclerosis.
Cardiovascular Research Center, CSIC-ICCC, IIB-SantPau, Barcelona, Spain.
D
D
de Gonzalo-Calvo
Lipid Unit and Molecular Research Laboratory, IIS Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain.
A
A
Cenarro
Biochemistry Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
M
M
Martínez-Bujidos
Cardiovascular Research Center, CSIC-ICCC, IIB-SantPau, Barcelona, Spain.
L
L
Badimon
Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain.
A
A
Bayes-Genis
Biochemistry Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
J
J
Ordonez-Llanos
Lipid Unit and Molecular Research Laboratory, IIS Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain.
F
F
Civeira
Cardiovascular Research Center, CSIC-ICCC, IIB-SantPau, Barcelona, Spain. Electronic address: cllorente@csic-iccc.org.
V
V
Llorente-Cortés
D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000097:blood* / Q000175:diagnosis*; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000175:diagnosis*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D055815:Young Adult
D015415:Biomarkers; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1
Atherosclerosis; Biomarker; Hypercholesterolemia; Soluble low-density lipoprotein receptor-related protein 1; Vascular smooth muscle cell