LDL receptor-related protein and the vascular wall: implications for atherothrombosis.

LDL receptor-related protein 1 (LRP1) is highly expressed in the vascular wall and is mainly associated with macrophages and vascular smooth muscle cells (VSMCs). Overexpression of LRP1 in atherosclerotic lesions has been demonstrated in several animal models and human lesions. Clinical studies have suggested a relation between alterations in LRP1 expression and coronary heart disease. Indeed, it has been demonstrated that LRP1 gene expression is increased in blood mononuclear cells from patients with coronary obstruction and that the LRP1 mRNA-protein expression ratio is altered in coronary patients. Taken together, these results seem to suggest that LRP1 may be a pivotal receptor in the etiology of atherosclerosis. Our group has contributed to the elucidation of the physiopathologic role of LRP1 in the vascular wall by demonstrating that LRP1-mediated, matrix-retained LDL internalization could be crucial for VSMC-foam cell formation, that LRP1 is upregulated by lipid during human atherosclerotic lesion progression, and that LRP1-mediated aggregated LDL uptake causes the prothrombotic transformation of the vascular wall. Therefore, LRP1 seems to play a pathologic function during atherosclerotic lesion progression; however, LRP1 also seems to be essential for embryonic development and for the maintenance of vascular integrity. The protective effect of LRP1 in the vessel wall seems to be mainly due to its role in controlling certain signaling pathways. In this review, we will focus on the description of the main physiopathologic functions of LRP1 in the vascular wall.

[1]  G. Bondjers,et al.  Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[2]  S. Pizzo,et al.  Coordinate Regulation of the α2-Macroglobulin Signaling Receptor and the Low Density Lipoprotein Receptor-related Protein/α2-Macroglobulin Receptor by Insulin* , 1999, The Journal of Biological Chemistry.

[3]  Yoshitaka Takahashi,et al.  Low Density Lipoprotein Receptor-related Protein Is Required for Macrophage-mediated Oxidation of Low Density Lipoprotein by 12/15-Lipoxygenase* , 2001, The Journal of Biological Chemistry.

[4]  P. Lenting,et al.  Activation of factor IX zymogen results in exposure of a binding site for low-density lipoprotein receptor-related protein. , 2000, Blood.

[5]  L. Badimón,et al.  LDL receptor-related protein mediates uptake of aggregated LDL in human vascular smooth muscle cells. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[6]  P. Quesenberry,et al.  Colony-stimulating factor-1 modulates alpha 2-macroglobulin receptor expression in murine bone marrow macrophages. , 1990, The Journal of biological chemistry.

[7]  V. Fuster,et al.  Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. , 1997, Circulation.

[8]  B. Binder,et al.  Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice. , 2000, Blood.

[9]  M. Gotthardt,et al.  LRP and PDGF signaling: a pathway to atherosclerosis. , 2004, Trends in cardiovascular medicine.

[10]  J. Miletich,et al.  The low-density lipoprotein receptor-related protein (LRP) mediates clearance of coagulation factor Xa in vivo. , 1998, Blood.

[11]  M. Shima,et al.  Cell Surface Heparan Sulfate Proteoglycans Participate in Factor VIII Catabolism Mediated by Low Density Lipoprotein Receptor-related Protein* , 2001, The Journal of Biological Chemistry.

[12]  A. Geyssant,et al.  Effect of dietary cholesterol on low density lipoprotein-receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and low density lipoprotein receptor-related protein mRNA expression in healthy humans , 1998, Lipids.

[13]  K. Werdan,et al.  The LDL receptor‐related protein (LRP1/A2MR) and coronary atherosclerosis – novel genomic variants and functional consequences , 2002, Human mutation.

[14]  R. Sakthivel,et al.  The Low Density Lipoprotein Receptor-related Protein/α2-Macroglobulin Receptor Regulates Cell Surface Plasminogen Activator Activity on Human Trophoblast Cells* , 1998, The Journal of Biological Chemistry.

[15]  J. Sevinsky,et al.  Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the tissue factor- dependent coagulation pathway , 1996, The Journal of cell biology.

[16]  P. Bornstein,et al.  The Low Density Lipoprotein Receptor-related Protein Modulates Levels of Matrix Metalloproteinase 9 (MMP-9) by Mediating Its Cellular Catabolism* , 2001, The Journal of Biological Chemistry.

[17]  G. Bondjers,et al.  Binding of low density lipoproteins by proteoglycans synthesized by proliferating and quiescent human arterial smooth muscle cells. , 1993, The Journal of biological chemistry.

[18]  G. Bu,et al.  Down-regulation of Monocyte Tissue Factor Mediated by Tissue Factor Pathway Inhibitor and the Low Density Lipoprotein Receptor-related Protein* , 1999, The Journal of Biological Chemistry.

[19]  Richard G. W. Anderson,et al.  LRP: Role in Vascular Wall Integrity and Protection from Atherosclerosis , 2003, Science.

[20]  L. Badimón,et al.  LDL Downregulates CYP51 in Porcine Vascular Endothelial Cells and in the Arterial Wall Through a Sterol Regulatory Element Binding Protein-2–Dependent Mechanism , 2001, Circulation research.

[21]  B. Gaëta,et al.  The 5'-flanking region of the alpha 2MR/LRP gene contains an enhancer-like cluster of Sp1 binding sites. , 1994, Biochimica et biophysica acta.

[22]  Sripriya Ranganathan,et al.  Platelet-derived Growth Factor (PDGF)-induced Tyrosine Phosphorylation of the Low Density Lipoprotein Receptor-related Protein (LRP) , 2002, The Journal of Biological Chemistry.

[23]  F. Kronenberg,et al.  Cellular uptake of lipoprotein[a] by mouse embryonic fibroblasts via the LDL receptor and the LDL receptor-related protein. , 1997, Journal of lipid research.

[24]  I. Fuki,et al.  Cell-surface heparan sulfate proteoglycans: dynamic molecules mediating ligand catabolism , 1997, Current opinion in lipidology.

[25]  M. Waknitz,et al.  Lipoprotein lipase induces catabolism of normal triglyceride-rich lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in vitro. A process facilitated by cell-surface proteoglycans. , 1993, The Journal of biological chemistry.

[26]  M. Mims,et al.  Altered ultrastructural morphology of self-aggregated low density lipoproteins: coalescence of lipid domains forming droplets and vesicles. , 1991, Journal of lipid research.

[27]  P. Quesenberry,et al.  Regulation of macrophage alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-gamma. , 1993, The Journal of clinical investigation.

[28]  C. Moldow,et al.  Apoptosis is associated with increased cell surface tissue factor procoagulant activity. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[29]  D. Strickland,et al.  The Cellular Internalization and Degradation of Hepatic Lipase Is Mediated by Low Density Lipoprotein Receptor-related Protein and Requires Cell Surface Proteoglycans (*) , 1995, The Journal of Biological Chemistry.

[30]  L. Badimón,et al.  Intracellular lipid accumulation, low‐density lipoprotein receptor‐related protein expression, and cell survival in vascular smooth muscle cells derived from normal and atherosclerotic human coronaries , 2004, European journal of clinical investigation.

[31]  L. Badimón,et al.  Low-Density Lipoprotein Upregulates Low-Density Lipoprotein Receptor-Related Protein Expression in Vascular Smooth Muscle Cells: Possible Involvement of Sterol Regulatory Element Binding Protein-2-Dependent Mechanism , 2002, Circulation.

[32]  T. Willnow.  The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism , 1999, Journal of Molecular Medicine.

[33]  Samin K. Sharma,et al.  Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. , 1996, Circulation.

[34]  S. Schulz,et al.  Low-density lipoprotein receptor-related protein in atherosclerosis development: up-regulation of gene expression in patients with coronary obstruction , 1998, Journal of Molecular Medicine.

[35]  K. Hirata,et al.  Immunohistochemical localization of endothelial cell-derived lipase in atherosclerotic human coronary arteries. , 2003, Cardiovascular research.

[36]  M. R. Halie,et al.  Association of smooth muscle cell tissue factor with caveolae. , 1996, Blood.

[37]  Richard G. W. Anderson,et al.  Platelet-derived Growth Factor Mediates Tyrosine Phosphorylation of the Cytoplasmic Domain of the Low Density Lipoprotein Receptor-related Protein in Caveolae* , 2002, The Journal of Biological Chemistry.

[38]  K. Werdan,et al.  Role of LDL receptor-related protein (LRP) in coronary atherosclerosis. , 2003, International journal of cardiology.

[39]  D. Strickland,et al.  LRP: a multifunctional scavenger and signaling receptor. , 2001, The Journal of clinical investigation.

[40]  R. Nieuwland,et al.  Elevated Numbers of Tissue-Factor Exposing Microparticles Correlate With Components of the Metabolic Syndrome in Uncomplicated Type 2 Diabetes Mellitus , 2002, Circulation.

[41]  J. Freyssinet,et al.  Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. , 2000, Circulation.

[42]  U. Beisiegel,et al.  Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP). , 1996, Journal of lipid research.

[43]  C. Drevon,et al.  Proteoglycans in macrophages: characterization and possible role in the cellular uptake of lipoproteins. , 1998, The Biochemical journal.

[44]  R. Czekay,et al.  Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity. , 2001, Molecular biology of the cell.

[45]  L. Badimón,et al.  Esterified cholesterol accumulation induced by aggregated LDL uptake in human vascular smooth muscle cells is reduced by HMG-CoA reductase inhibitors. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[46]  S. Moestrup,et al.  Distribution of the α2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues , 1992, Cell and Tissue Research.

[47]  T. Nikkari,et al.  Expression of LDL receptor, VLDL receptor, LDL receptor-related protein, and scavenger receptor in rabbit atherosclerotic lesions: marked induction of scavenger receptor and VLDL receptor expression during lesion development. , 1998, Circulation.

[48]  A. Schwartz,et al.  The Low Density Lipoprotein Receptor-related Protein Can Function Independently from Heparan Sulfate Proteoglycans in Tissue Factor Pathway Inhibitor Endocytosis* , 1996, The Journal of Biological Chemistry.

[49]  S. L. Gonias,et al.  Embryonic Fibroblasts That Are Genetically Deficient in Low Density Lipoprotein Receptor-related Protein Demonstrate Increased Activity of the Urokinase Receptor System and Accelerated Migration on Vitronectin* , 1997, The Journal of Biological Chemistry.

[50]  M. Penn,et al.  Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation. , 2000, Blood.

[51]  T. Hayek,et al.  Lesioned low density lipoprotein in atherosclerotic apolipoprotein E-deficient transgenic mice and in humans is oxidized and aggregated. , 1995, Biochemical and biophysical research communications.

[52]  U. Pendurthi,et al.  Catabolism of Factor VIIa Bound to Tissue Factor in Fibroblasts in the Presence and Absence of Tissue Factor Pathway Inhibitor* , 1999, The Journal of Biological Chemistry.

[53]  Yonghe Li,et al.  Low Density Lipoprotein (LDL) Receptor-related Protein 1B Impairs Urokinase Receptor Regeneration on the Cell Surface and Inhibits Cell Migration* , 2002, The Journal of Biological Chemistry.

[54]  L. Badimón,et al.  Differential cholesteryl ester accumulation in two human vascular smooth muscle cell subpopulations exposed to aggregated LDL: effect of PDGF-stimulation and HMG-CoA reductase inhibition. , 1999, Atherosclerosis.

[55]  T. Kodama,et al.  Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions. , 1994, The Journal of clinical investigation.

[56]  S. Moestrup,et al.  Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. , 1992, The Journal of biological chemistry.

[57]  M. Bogdanov,et al.  Reversible Topological Organization within a Polytopic Membrane Protein Is Governed by a Change in Membrane Phospholipid Composition* , 2003, Journal of Biological Chemistry.

[58]  L. Badimón,et al.  Differential Role of Heparan Sulfate Proteoglycans on Aggregated LDL Uptake in Human Vascular Smooth Muscle Cells and Mouse Embryonic Fibroblasts , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[59]  Lina Badimon,et al.  Human Coronary Smooth Muscle Cells Internalize Versican-Modified LDL Through LDL Receptor–Related Protein and LDL Receptors , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[60]  J. Herz,et al.  Structure of the low-density lipoprotein receptor-related protein (LRP) promoter. , 1989, Biochimica et biophysica acta.

[61]  S. Vandenberg,et al.  Transcriptional regulation of LDL receptor‐related protein by IFN‐γ and the antagonistic activity of TGF‐β1 in the RAW 264.7 macrophage‐like cell line , 1996, Journal of leukocyte biology.

[62]  I. Goldberg,et al.  Heparan sulfate proteoglycan-mediated uptake of apolipoprotein E-triglyceride-rich lipoprotein particles: a major pathway at physiological particle concentrations. , 1997, Biochemistry.

[63]  L. Badimón,et al.  Aggregated Low-Density Lipoprotein Uptake Induces Membrane Tissue Factor Procoagulant Activity and Microparticle Release in Human Vascular Smooth Muscle Cells , 2004, Circulation.

[64]  D. Webb,et al.  Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and matrigel invasion. , 2000, Journal of cell science.

[65]  M. Brown,et al.  Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[66]  L. Fong,et al.  Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages. , 1998, Journal of lipid research.