Scavenger receptors are membrane glycoproteins that bind diverse ligands including lipid particles, phospholipids, apoptotic cells and pathogens. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) is increasingly linked to atherosclerotic plaque formation. Transgenic mouse models for LOX-1 overexpression or gene knockout suggests that LOX-1 contributes to atherosclerotic plaque formation and progression. LOX-1 activation by oxidized LDL (low-density lipoprotein) binding stimulates intracellular signalling, gene expression and production of superoxide radicals. A key question is the role of leucocyte LOX-1 in pro-atherogenic lipid particle trafficking, accumulation and signalling leading to differentiation into foam cells, necrosis and plaque development. LOX-1 expression is elevated within vascular lesions and a serum soluble LOX-1 fragment appears diagnostic of patients with acute coronary syndromes. LOX-1 is increasingly viewed as a vascular disease biomarker and a potential therapeutic target in heart attack and stroke prevention.

INTRODUCTION

Atherosclerosis is a chronic inflammatory disease characterized by lipid-laden lesions within arterial blood vessel walls [1]. Increased calorific intake, genetics and environmental factors can elevate serum LDL (low-density lipoprotein) particle levels and subsequent LDL accumulation within blood vessel walls (Figure 1). These accumulated LDLs become chemically modified within the vascular intima leading to recognition by different vascular cell types. Modified LDLs can cause endothelial activation and dysfunction [2]. Migratory vascular leucocytes also recognize modified LDLs and such interactions regulate formation of lipid-laden foam cells and necrotic cell debris within atherosclerotic plaques and lesions [3].

Schematic overview of vascular LDL and OxLDL accumulation

Figure 1
Schematic overview of vascular LDL and OxLDL accumulation

LDL diffusion into blood vessel walls leads to modification, oxidization and OxLDL appearance. OxLDL is a pro-atherogenic factor that initiates endothelial cell activation and dysfunction via LOX-1. Endothelial surface adhesion molecules stimulate trans-endothelial migration by leucocytes. Resulting macrophages recognize modified lipid particles via membrane-bound receptors, differentiating into lipid-laden foam cells forming part of the necrotic core within atherosclerotic plaques. LOX-1 expression and activation is also implicated in latter stages of plaque destabilization and rupture producing thrombotic complications.

Figure 1
Schematic overview of vascular LDL and OxLDL accumulation

LDL diffusion into blood vessel walls leads to modification, oxidization and OxLDL appearance. OxLDL is a pro-atherogenic factor that initiates endothelial cell activation and dysfunction via LOX-1. Endothelial surface adhesion molecules stimulate trans-endothelial migration by leucocytes. Resulting macrophages recognize modified lipid particles via membrane-bound receptors, differentiating into lipid-laden foam cells forming part of the necrotic core within atherosclerotic plaques. LOX-1 expression and activation is also implicated in latter stages of plaque destabilization and rupture producing thrombotic complications.

An initial event in atherosclerosis is LDL conversion into modified LDL or OxLDL (oxidized LDL) by factors including radicals, transition metals and lipoxygenases, causing cleavage of polyunsaturated fatty acids within the LDL particle. The resulting shorter chain reactive aldehydes become chemically conjugated to lysine residues on the apoB (apolipoprotein B)-100 protein component of LDL; this OxLDL now contains an overall greater net negative charge that alters receptor-mediated interactions [4,5].

OxLDL binding to scavenger receptors [e.g. LOX-1 (lectin-like OxLDL receptor-1)] stimulates endothelial expression and secretion of pro-atherogenic enzymes [e.g. MMPs (matrix metalloproteases)]; superoxide production is also stimulated, reducing local nitric oxide levels [6]. Elevating MCP-1 (monocyte chemotactic protein-1) and M-CSF (macrophage colony-stimulating factor) act as chemoattractants that actively stimulate progression towards plaque development. Pro-inflammatory conditions elevate expression of vascular adhesion molecules [ICAM-1 (intercellular adhesion molecule 1), P-selectin, E-selectin, PECAM-1 (platelet/endothelial cell adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1)] which promote recruitment, attachment and infiltration of monocytes from the circulating bloodstream into the vessel wall [7]. These vascular proteins can interact with leucocyte β2 integrin, VLA-1 (very late antigen 1) and PECAM-1. Migratory monocytes within the vasculature differentiate into macrophages in the presence of M-CSF secreted by the endothelium. These leucocytes also express scavenger receptors which mediate OxLDL recognition and uptake [8]. Macrophage lipid accumulation causes foam-cell formation leading to cell death and appearance of a lipid-rich necrotic core within the lesion (Figure 1). Cytokines can further stimulate proliferation and migration of smooth muscle cells to form a fibrous cap enclosing this necrotic lipid core thus forming an advanced fibrous lesion. Further modifications of the lesion by calcification or plaque rupture leads to atherothrombosis [9].

A structurally diverse protein supergroup called scavenger receptors mediate the cellular uptake of modified lipoproteins [10]. Scavenger receptors are expressed by endothelial cells, macrophages and smooth muscle cells and mediate recognition, internalization and physiological responses to a wide range of ligands including phospholipids, lipoprotein particles, apoptotic cells and pathogens. The focus of the present review will be LOX-1 (or OLR1) [11,12]. LOX-1 was originally identified as the major endothelial scavenger receptor but was subsequently detected on other cell types. An atherosclerosis mouse model shows that LOX-1 deletion reduced plaque formation [13], indicating that LOX-1 is a pro-atherogenic factor.

LOX-1 GENETICS AND ANIMAL MODELS

The LOX-1 protein is in the class E scavenger receptor subgroup; the human gene is within a C-type lectin gene cluster on chromosome 12 that contains immune recognition receptor genes [14]. LOX-1 gene expression is regulated by cytokines, intracellular signalling and shear stress [15,16]. In resting vascular tissues, LOX-1 mRNA and protein levels are low but elevated under pro-inflammatory disease states [17,18]. LOX-1 was first identified as an endothelial-specific scavenger receptor [19] but was subsequently detected on macrophages [20], smooth muscle cells, monocytes [21] and platelets [22].

In early atherosclerotic lesions, LOX-1 levels are elevated both within the intima and in the endothelium surrounding the lesion, suggesting that LOX-1 is involved in initiation and formation of atherosclerotic plaques [17]. A LOX-1-null mouse model provides strong evidence that LOX-1 expression causes predisposition to atherosclerotic plaque formation and development [13]. Double LDL-receptor- and LOX-1-null mice fed a high cholesterol diet exhibited significantly reduced atherosclerotic plaque formation in comparison with LDL-receptor-null mice alone [13]. Thus the OxLDL and LOX-1 interaction accelerates atherosclerotic plaque formation and progression. A different mouse model with overexpression of LOX-1 in an apoE (apolipoprotein E)-deficient background increases atherosclerotic plaque incidence [23], consistent with a role for LOX-1 in plaque development and progression.

Human genetic linkage studies implicate LOX-1 polymorphisms in cardiovascular disease susceptibility. Seven SNPs (single nucleotide polymorphisms; six non-coding, one coding) within the LOX-1 gene have been found [24]. One such SNP promotes production of a truncated LOX-1 splice isoform (termed LOXIN) lacking part of the extracellular domain [25]. LOXIN expression confers increased resistance to OxLDL-induced macrophage apoptosis [25], indicative of protection against atherosclerosis. Conversely, a LOX-1 G501C polymorphism that encodes a K167N substitution may increase the risk of myocardial infarction [26].

LOX-1 STRUCTURE AND LIGAND RECOGNITION

LOX-1 is a type II integral membrane glycoprotein with a short N-terminal cytoplasmic domain, a single transmembrane domain, a short ‘neck’ or stalk region and an extracellular C-type lectin-like fold (Figure 2). This C-type lectin-like fold is highly conserved within LOX-1 mammalian orthologues, notably at six cysteine residues which underpin the lectin-like fold by forming three intramolecular disulfide bonds [27]. N-glycosylation of LOX-1 regulates protein folding within the endoplasmic reticulum, secretory transport to the plasma membrane and ligand recognition [28].

LOX-1 structure

Figure 2
LOX-1 structure

(A) Schematic representation of LOX-1 derived from structural studies [30,62,63]. This type II membrane glycoprotein consists of a short cytoplasmic N-terminus (residues 1–33), a single transmembrane domain (TMD) and an extracellular domain comprising a potential coiled-coil helical region (residues 61–139) next to a C-type lectin-like fold (residues 140–273). (B) The C-type lectin-like domain has inherent dimerization capability through an intermolecular disulfide linkage at Cys140. It is postulated that the ‘neck’ region regulates further LOX-1 oligomerization. (C, D) Promiscuity in ligand recognition by LOX-1 is revealed by transfected HeLa cells expressing human LOX-1 showing binding to (C) OxLDL and (D) apoptotic bodies (indicated by an asterisk). In the panels shown, the colours are (C) LOX-1 (green) and OxLDL (red), (D) LOX-1 (green) and apoptotic body stained with annexin V (red) and DAPI (blue). In both panels, nuclear DNA is stained with DAPI (blue). (D) is reproduced with permission from Murphy, J.E., Tacon, D., Tedbury, P.R., Hadden, J.M., Knowling, S., Sawamura, T., Peckham, M., Phillips, S.E., Walker, J.H. and Ponnambalam, S. (2006), Biochem. J., 393, 107–115, © the Biochemical Society. Scale bar=10 μm.

Figure 2
LOX-1 structure

(A) Schematic representation of LOX-1 derived from structural studies [30,62,63]. This type II membrane glycoprotein consists of a short cytoplasmic N-terminus (residues 1–33), a single transmembrane domain (TMD) and an extracellular domain comprising a potential coiled-coil helical region (residues 61–139) next to a C-type lectin-like fold (residues 140–273). (B) The C-type lectin-like domain has inherent dimerization capability through an intermolecular disulfide linkage at Cys140. It is postulated that the ‘neck’ region regulates further LOX-1 oligomerization. (C, D) Promiscuity in ligand recognition by LOX-1 is revealed by transfected HeLa cells expressing human LOX-1 showing binding to (C) OxLDL and (D) apoptotic bodies (indicated by an asterisk). In the panels shown, the colours are (C) LOX-1 (green) and OxLDL (red), (D) LOX-1 (green) and apoptotic body stained with annexin V (red) and DAPI (blue). In both panels, nuclear DNA is stained with DAPI (blue). (D) is reproduced with permission from Murphy, J.E., Tacon, D., Tedbury, P.R., Hadden, J.M., Knowling, S., Sawamura, T., Peckham, M., Phillips, S.E., Walker, J.H. and Ponnambalam, S. (2006), Biochem. J., 393, 107–115, © the Biochemical Society. Scale bar=10 μm.

LOX-1 is likely to form a homodimer via an interchain disulfide bond between Cys140 residues [29]. LOX-1 homodimers appear to further interact through non-covalent interactions that promote multimerization and better OxLDL binding. LOX-1 multimerization is dependent on the ‘neck’ region [30] and density at the plasma membrane [31]. Bovine LOX-1 is cleaved within the ‘neck’ region to release a soluble LOX-1 fragment [32]. PMSF inhibits such proteolysis indicating a role for a serine protease; this may also be analogous to cell-surface receptor cleavage by secretases on targets such as Notch and the amyloid precursor protein.

LOX-1 binds structurally diverse ligands, similar to other scavenger receptors. Proteins such as toll-like receptors and scavenger receptors have broad ligand specificity and are called pattern recognition receptors. The precise OxLDL epitope recognised by LOX-1 is not known but is thought to be peptide-based [33]. LOX-1 recognizes other modified lipoprotein particles including hypochlorite-modified high-density lipoprotein [34] but not native LDL [33]. LOX-1 also binds anionic polymers such as polyinosinic acid and carrageenan [33], anionic phospholipids including phosphatidylserine [35], apoptotic bodies, aged cells [36], activated platelets [37], AGEs (advanced glycation end-products) [38] and both gram-positive and gram-negative bacteria [39] (Figure 2).

Intriguingly, the 140 residue C-type lectin-like domain confers recognition of these diverse ligands [40] (Figure 2). Ligand binding by the LOX-1 extracellular domain is dependent on both protein epitopes and carbohydrate moieties, especially positively charged residues 270–273 at the extreme C-terminus and neutral hydrophilic residues between Cys168 and Cys239. The LOX-1 ‘neck’ region of LOX-1 appears non-essential for OxLDL recognition but regulates receptor oligomerization, ligand affinity and uptake (R.S. Vohra and S. Ponnambalam, unpublished work).

LOX-1-REGULATED INTRACELLULAR SIGNALLING

LOX-1 activation by ligands can lead to intracellular signalling causing endothelial activation or dysfunction, cell proliferation, apoptosis and atherosclerosis. In the healthy adult resting state, LOX-1 is expressed at relatively low levels; however, LOX-1 levels are elevated under pathological conditions including hypertension [41], hyperlipidaemia [42], diabetes [43] and atherosclerosis [17]. These pathological states elevate LOX-1 levels via intracellular signalling and transcription factor activation causing increased LOX-1 mRNA synthesis. Importantly LOX-1 levels are elevated by OxLDL binding [44], indicating that proinflammatory conditions create positive-feedback loops that enhance vascular dysfunction. LOX-1 mRNA and protein levels are also elevated by pro-inflammatory stimuli such as TNFα (tumour necrosis factor α) [15], TGF-β (transforming growth factor-β) [45], phorbol ester [15], angiotensin II [46] and fluid shear stress [16]. Although TGF-β inhibits SR-A (scavenger receptor type A) and CD36 scavenger receptor gene expression, it stimulates LOX-1 gene expression in the endothelium, smooth muscle and leucocytes [47]. Angiotensin II, a peptide agonist and pro-atherogenic factor, elevates LOX-1 levels through type I angiotensin receptor activation; such LOX-1 gene expression is blocked by losartan, an angiotensin II type 1 receptor inhibitor [42]. Endothelin-1, a potent vasoconstrictor and pro-atherogenic factor in coronary heart disease, also stimulates LOX-1 gene expression [48]. LOX-1 gene expression is also stimulated via a redox-sensitive pathway by superoxide radicals generated by hypoxanthine, xanthine oxidase and hydrogen peroxide [49]. These findings further strengthen links between circulating pro-atherogenic factors (e.g. endothelin-1, TNFα) and LOX-1 gene expression in atherosclerosis development and progression.

LOX-1 binding to OxLDL rapidly elevates ROS (reactive oxygen species) levels including superoxide anions and hydrogen peroxide via activation of a membrane-bound NADPH oxidase [50] (Figure 3). Multiple downstream events are activated via secondary messengers including NF-κB (nuclear factor κB) nuclear translocation and concomitant gene expression. Superoxide anions oxidize and inactivate nitric oxide, an important anti-atherogenic factor in vasodilation and blood pressure control. Elevated ROS levels also inhibit endothelial cytochrome P450, which catalyses production of endothelial-derived hyperpolarization factor, another vascular tone regulator [51]. ROS modifies accumulated vascular LDL to OxLDL, thus activating LOX-1 generating a continuous feedback loop that promotes atherosclerosis.

Model for LOX-1 signalling and trafficking

Figure 3
Model for LOX-1 signalling and trafficking

LOX-1 activation by ligands leads to intracellular signalling, causing rapid elevation of ROS levels via membrane-bound NADPH oxidase. Downstream activation of p38 MAPK and PI3K events are linked to NF-κB translocation and cellular apoptosis via an increased Bax/Bcl-2 ratio. NF-κB regulates vascular expression of P-selectin, VCAM-1, ICAM-1, MCP-1 and M-CSF which stimulate macrophage accumulation. Although LOX-1 probably mediates OxLDL internalization, this mechanism has not been elucidated and cell-type differences are likely. A key question is the balance between dissociation, recycling and degradation of the receptor–ligand complex as it progresses from the endosome (E), late endosome (LE) and lysosome (L).

Figure 3
Model for LOX-1 signalling and trafficking

LOX-1 activation by ligands leads to intracellular signalling, causing rapid elevation of ROS levels via membrane-bound NADPH oxidase. Downstream activation of p38 MAPK and PI3K events are linked to NF-κB translocation and cellular apoptosis via an increased Bax/Bcl-2 ratio. NF-κB regulates vascular expression of P-selectin, VCAM-1, ICAM-1, MCP-1 and M-CSF which stimulate macrophage accumulation. Although LOX-1 probably mediates OxLDL internalization, this mechanism has not been elucidated and cell-type differences are likely. A key question is the balance between dissociation, recycling and degradation of the receptor–ligand complex as it progresses from the endosome (E), late endosome (LE) and lysosome (L).

LOX-1 activation stimulates gene expression, e.g. activation of NF-κB pro-inflammatory regulator(s) [5254]. ROS can activate two signal transduction pathways involving either p38 MAPK (mitogen-activated protein kinase) or PI3K (phosphoinositide 3-kinase), both causing NF-κB activation and enabling nuclear translocation and subsequent regulation of pro-inflammatory gene expression [55] (Figure 3). Blocking LOX-1 activation with a neutralizing antibody in a rat model for ischaemia–reperfusion injury also inhibited p38 MAPK activation. LOX-1-null mice showed reduced expression of the redox-sensitive NF-κB p65 subunit [13], linking LOX-1 activation to NF-κB-regulated gene expression. LOX-1 activation by OxLDL also stimulates cellular apoptosis via an increased Bax (Bcl-2-associated X protein)/Bcl-2 ratio and NF-κB activation [56]. This is important in atherosclerosis progression as OxLDL-induced apoptosis of smooth muscle cells leads to plaque destabilization and rupture. NF-κB-related gene products define a class of transcriptional regulators which regulate expression of vascular genes including P-selectin, VCAM-1, ICAM-1, MCP-1 and M-CSF. LOX-1 gene expression in response to OxLDL is inhibited by antisense oligonucleotides and abolishes MAPK activation [57]; this pathway is important for pro-atherogenic gene expression. Thus modulation of LOX-1 levels may be one therapeutic route in attenuating early events in atherosclerosis.

LOX-1 activation can elevate CD40 and CD40L (CD40 ligand) levels, key pro-inflammatory factors [58]. CD40-regulated intracellular signalling is an early immune response event and stimulates cytokine and chemokine secretion. LOX-1-mediated stimulation of CD40/CD40L levels occurs via PKCα (protein kinase Cα) activation and is also notable for pro-inflammatory gene expression e.g. TNFα and P-selectin.

LOX-1 TRAFFICKING AND LIPID ACCUMULATION

Although LOX-1/OxLDL activation and intracellular signalling have been extensively studied, it is unclear whether similar pathways are activated upon LOX-1 binding to other ligands including phospholipids, leucocytes, platelets, apoptotic bodies or pathogens. LOX-1 could simply be a vascular sensor but also promote ligand internalization, accumulation and/or clearance via lysosomal degradation (Figure 3). Different studies indicate that LOX-1 mediates OxLDL internalization; intracellular OxLDL levels are reduced by anti-LOX-1 antibodies that block OxLDL recognition in endothelial cells [59] and oligonuclotide-mediated LOX-1 gene repression in macrophages reduces internal lipid-rich accumulation [60]. Thus LOX-1 is required for intracellular trafficking of vascular OxLDL. Such trafficking must vary between different cell types since endothelial cells do not accumulate lipid, unlike macrophages. Alternatively, endothelial-specific proteases and lipases could mediate active degradation of internalized OxLDL, but such factors are absent in leucocytes.

An intriguing question in membrane-receptor function is the co-ordination of cell signalling with membrane trafficking. For example, cell-surface activation of receptor tyrosine kinases such as EGFR (epidermal growth factor receptor) or the scatter factor receptor, c-Met, indicates prolonged signalling by the receptor–ligand complex both at the plasma membrane and after trafficking to downstream endosomes [61]. This signalling probably differs depending on the location of the receptor–ligand complex, e.g. at the plasma membrane or early endosomes. This parameter is further regulated by local concentrations of membrane-associated adaptors, protein kinases and phospholipids. Extending such a scenario to LOX-1 trafficking and signalling suggests that physiological vascular responses to OxLDL could be regulated by expression of cell-specific signalling, trafficking and proteolytic factors positioned within the endocytic pathway.

CONCLUDING REMARKS

The LOX-1 scavenger receptor is now classified as a key pro-atherogenic molecule that initiates multiple signalling cascades to activate diverse gene expression regulating cellular activation, dysfunction, proliferation and apoptosis. Further studies on the LOX-1 membrane protein and its interactions with diverse ligands, regulation of subsequent trafficking and signalling will provide greater insights into protein function in animal health, disease and therapeutic approaches.

Our work is supported by a British Heart Foundation project grant (to S. P., J. H. W and S. H. V.), a Clinical Research Fellowship from the York Hospitals NHS Foundation Trust and a Royal College of Surgeons of England Research Fellowship (to R. S. V.), a BBSRC (Biotechnology and Biological Sciences Research Council) PhD studentship (to J. E. M) and Wellcome Trust Equipment awards for biophysics and bioimaging.

Abbreviations

     
  • Bax

    Bcl-2-associated X protein

  •  
  • CD40L

    CD40 ligand

  •  
  • ICAM-1

    intercellular adhesion molecule 1

  •  
  • LDL

    low-density lipoprotein

  •  
  • LOX-1

    lectin-like oxidized LDL receptor-1

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MCP-1

    monocyte chemotactic protein-1

  •  
  • M-CSF

    macrophage colony-stimulating factor

  •  
  • NF-κB

    nuclear factor κB

  •  
  • OxLDL

    oxidized LDL

  •  
  • OLR1

    OxLDL (lectin-like) recceptor 1

  •  
  • PECAM-1

    platelet/endothelial cell adhesion molecule 1

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • ROS

    reactive oxygen species

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • TGF-β

    transforming growth factor-β

  •  
  • TNFα

    tumour necrosis factor α

  •  
  • VCAM-1

    vascular cell adhesion molecule 1

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