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CD36 and macrophages in atherosclerosis

 
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Abstract

CD36 is a multi-ligand scavenger receptor present on the surface of a number of cells such as platelets, monocytes/macrophages, endothelial and smooth muscle cells. Monocyte/macrophage CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and endocytose oxidized low density lipoproteins (OxLDL), and it is implicated in the formation of foam cells. However, the significance of CD36 in atherosclerosis has recently been called into question by different studies, and therefore its exact role still needs to be clarified. The aim of this article is to carefully review the importance of CD36 as an essential component in the pathogenesis of atherosclerosis.

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Time for primary review 21 days

Atherosclerosis is a progressive chronic inflammatory disease characterised by a gradual thickening and hardening of arteries that ultimately leads to a reduction in the lumen diameter and potentially to ischemia following plaque rupture. A first stage of the disease is the presence of dysfunctional endothelial cells (EC) which via activated adhesion molecules and expressed chemokines recruit circulating monocytes and a subpopulation of lymphocytes (CD4/CD8) into the intima. Endothelial dysfunction may be induced by oxidized low density lipoproteins (OxLDL). Indeed, LDL when infiltrating into the intima can be readily oxidized by resident macrophages or endothelial cells. Moreover, C-reactive protein (CRP) and OxLDL can act synergistically to increase monocytes inflammatory properties (through MCP-1, PGE2, MMP-1 production) and attract further circulating monocytes through the release of MCP-1 to adhere to the activated dysfunctional endothelial cells and extravasate to the intima to scavenge OxLDL [1]. One of the involvements of CD36 in lesion development is its ability to bind and endocytose OxLDL into macrophages, as a scavenger receptor, and ultimately be implicated in the differentiation of resident macrophages into foam cells that constitute the atherosclerotic lesion core.

CD36 is an 88-kD membrane glycoprotein that was first identified on monocytes by monoclonal antibody OKM5 [2] and then subsequently isolated from blood platelets [3,4]. This membrane glycoprotein is expressed by many cell-types including microvasculature endothelial [5] and smooth muscle cells (SMC) [6]. Functional and structural characterisation showed CD36 to be a member of the scavenger receptor class B family with a capacity to bind OxLDL as well as various other ligands. The importance of monocytic CD36 in the initiation and perpetuation of atherosclerotic lesions was shown over this past decade by its effect in significantly reducing the size of vascular lesions when inactivated in ApoE deficient animals, and by its substantial capacity to endocytose OxLDL. However, the role of CD36 as a critical player in modulating the size of atherosclerotic lesions has recently been challenged by further studies in ApoE deficient mice. The aim of this study is to carefully review the importance of CD36 as a critical component in the pathogenesis of atherosclerosis.

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1 Structure and functional studies performed on CD36

The CD36 gene is more than 46 kb in size and is located on band q11.2 of chromosome 7 [7,8]. Out of the 15 exons that are present in this gene only part of exon 3, exons 4 to 13 and part of exon 14 code for the CD36 protein. The remaining segment exons make up the 3′- and 5′ untranslated region (3′and 5′-UTR). It is of great interest to note, in view of the expression of CD36 by a wide number of cells, that exons 1a, 1b, 1c, 1e and 1f have been described as alternative first exons with tissue-specific regulation [8–12] (Fig. 1 ).

Fig. 1
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Fig. 1

Schematic representation of CD36 gene. CD36 gene comprises 15 exons. The 5′-untranslated region (5′-UTR) consists of exons 1a, 1b, 1c, 1e, 1f, 2 and part of exon 3. The remaining part of exon 3, exons 4 to 13 and part of exon 14 encode the CD36 protein whilst the remaining segment of exon 14 and exon 15 make up the 3′-untranslated region (3′-UTR).

CD36 protein is predicted to adopt a ditopic configuration with the presence of an extracellular domain flanked by two transmembrane and two cytoplasmic domains. The extracellular region is rich in N-linked glycosylation sites and bears a hydrophobic domain (located between amino acids 184 to 204) that could potentially interact with the plasma membrane, a proline rich region (located between amino acids 242 to 333) [13] (Fig. 2A) and several identified functional domains. Indeed, a domain located between amino acids 155 to 183 was identified to bind OxLDL [14], advanced glycated products (AGE) [15] and the growth hormone (GH)-releasing peptides hexarelin and EP80317 [16]. Other OxLDL binding sites on CD36 were reported for domains encoded by amino acids 28–93 and possibly 120–155 [17]. Interestingly, 2 domains on CD36, namely amino acids 155 to 183 and 93 to120 also referred to as CLESH (CD36 LIMP-II Emp sequence homology) are potentially implicated in the binding and endocytosis of apoptotic neutrophils. This process of endocytosis takes place in tandem with the integrin complex αvβ3 and the CD36 ligand thrombospondin-1 [18–21] (Fig. 2B). Other domains present on CD36, such as those present on amino acids 139–184 and more particularly to 146–164 or 145–171 that mediate the binding with PfEMP-1, a membrane protein specifically expressed by P falciparum infected erythrocytes, are not related to the topic of this review and hence will not be further discussed.

Fig. 2
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Fig. 2

Schematic representation of CD36 protein (A) primary structure of CD36 with tramsmembrane domain (yellow/orange box), hydrophobic region (light blue) and proline-rich region (dark blue). The ten predicted N-linked glycosylated sites and ten cysteines are shown. (B) 3D representation of CD36 receptor on cellular membrane. The CLESH (CD36 LIMP-II Emp sequence homology) motif and PfEMP-1 site are the binding sites for thrombospondin-1/-2 (TSP-1 and TSP-2) and P. falciparum erythrocyte membrane protein-1 (P. falciparum PfEMP-1) respectively. 155–183 amino acid region is the binding site for OxLDL, AGE, growth hormone-releasing peptide heraxelin (GHRP), monoclonal antibodies (MoAbs), and apoptotic neutrophils.

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2 Transcriptional changes induced by OxLDL via CD36

OxLDL has been shown to bind to macrophage CD36 via its lipid moiety [22] and to other scavenger receptors via its apoprotein moiety. Results show that oxidized phospholipids covalently bound to apoB or in lipid phase are recognized by CD36 and appear to be implicated in the high affinity docking of OxLDL to CD36 [23]. Structural characteristic needed from oxidized phospholipids to bind with high affinity to CD36 is a phospholipid with a sn-2 acyl group incorporating a terminal γ-hydroxy(or oxo)-α,β-unsaturated carbonyl (oxPCCD36), formed during LDL oxidation [24]. Using computational modeling, OxLDL binding domain on CD36 was shown to contain a structure with a positively charged groove formed by a lysine cluster, which specifically interact with negatively charged ligands such as OxLDL [25]. OxLDL bound to CD36 is then endocytosed through a raft mediated-pathway that appears to be independent from caveolae, caveolin-1 and clathrin-mediated internalization [26].

Endocytosed OxLDL induces important and complex transcriptional changes in monocytes-derived-macrophages and that includes an up-regulation of the CD36 expression [27]. Following OxLDL stimulation, transcription factor PPARγ is transactivated via a p38MAP kinase-dependent pathway [28] and heterodimerizes with the retinoid X receptor (RXR). The PPARγ:RXRα complex binds directly to PPAR response elements (PPREs) in the CD36 promoter and induces an increase of CD36 expression [29]. Moreover, OxLDL-mediated CD36 up-regulation was reported to involve initial activation of protein kinase C (PKC) with subsequent PPARγ activation [30]. Protein kinase B (PKB) has also been shown to be implicated in CD36 up-regulation in response to OxLDL [31]. Indeed, over-expression of PKB in macrophages stimulated the CD36 promoter as well as a PPARγ element-driven reporter gene [31] (Fig. 3 ). CD36 up-regulation by OxLDL was recently shown to be necessary for the differentiation of macrophages into foam cells [32]. In this study, it was observed that (1) CD36 was associated with a signaling complex containing Lyn and MEKK2 and (2) OxLDL-specific activation of MAP kinases JNK1 and JNK2 was mediated by CD36 [32] (Fig. 3). Interestingly, PPARγ can also induce CD36 expression in vascular SMC that can then be implicated in the differentiation of SMC into foam cells [33]. It is worth noting that PPARγ by inducing ABCA1 expression also regulates cholesterol efflux from macrophages through a transcriptional cascade mediated by the nuclear receptor LXRα [34] (Fig. 3). OxLDL stimulation induces the activation of the transcription factor NFκB in macrophages [35] through a mechanism that is dependent on CD36 and PKC [36] (Fig. 3). Indeed, OxLDL triggers the secretion of inflammatory cytokines such as TNFα/β, IL-1β, IL-6, and interferon beta and gamma (IFNβ/γ) whose expressions are significantly decreased in CD36-deficient macrophages [37] (Fig. 3). Moreover, apoptosis occurring in macrophages and/or foam cells induced by OxLDL occurs via a mechanism that is dependent on CD36 and on the activation of caspase-3 [38].

Fig. 3
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Fig. 3

Schematic representation of the effect of OxLDL on macrophages via CD36 scavenger receptor. OxLDL bind to CD36 and trigger the activation of transcription factor PPARγ, which leads to an increased presentation of the receptor to the macrophage surface. NFκB is also targeted by OxLDL stimulation inducing the synthesis of diverse cytokines. OxLDL stimulation in macrophages triggers the activation of kinases related to CD36 such as Lyn, MEKK2, JNK1 and JNK2.

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3 Involvement of CD36 and OxLDL in atherosclerotic lesions

CD36 and Scavenger Receptor class A (SRA I/II) are the principal receptors responsible for the binding and uptake of modified LDL in macrophages. Indeed, together the aforesaid account for 75 to 90% of the uptake and degradation of acetylated and oxidized LDL [39]. Several lines of evidences, both in vitro and in animal models, show the capacity of CD36 to bind and endocytose OxLDL and to be implicated in atherosclerotic lesions formation. The very first observations are linked to the work of Endemann et al., who using a human epithelial kidney cell line (HEK293) transfected with CD36, showed the capacity of the scavenger receptor to bind specifically OxLDL [40]. An absence of CD36 on monocytes, as observed in a small percentage of individuals in the Japanese population, results in 40 to 50% less OxLDL binding to monocytes-derived-macrophages compared to macrophages from normal subjects [41]. This lowered level of binding and uptake of OxLDL is also observed when CD36 binding sites are blocked by a specific monoclonal antibody, such as OKM5, which reduced OxLDL binding to normal macrophages by 50% [41]. The same type of results with OKM5 blocking CD36 functional sites is observed when using monocytic cell line (THP-1) treated with PMA [40]. Investigation of monocytes/macrophages from CD36-deficient human subjects has not to this date clearly indicated if such individuals are less or more prone to atherosclerotic lesions and coronary diseases. However, work on a murine model with a combined ApoE and CD36 deficiency, or double knockout, has shown to be quite interesting in investigating the role of CD36 in atherosclerotic lesions under different time periods. One should note that ApoE deficiency, in mice with a Balbc background, results in animals having very high circulating cholesterol levels and lesions developing at a very fast pace compared to the wild-type. Macrophages derived from 12-week old mice with a double CD36/ApoE knockout displayed a very significant decrease (76.5%) of aortic tree lesion size when compared to single knockout ApoE mice. Moreover, macrophages of these double knockouts bound and internalized 60% less OxLDL compared to ApoE deficient mice [42]. These results on double knockout mice do suggest that a macrophage CD36 deficiency does affect the size of vascular lesions. Reintroduction of CD36 in the ApoE/CD36-deficient mice, using stem cell transfer, resulted as one would expect in an increase in lesion area [43]. The effects of macrophage CD36 deficiency did not lapse with the age of the animals since work on 35-week old CD36/ApoE double knockout mice also showed smaller atherosclerotic lesions compared to ApoE control mice [44]. Strong evidence does appear to be present to show that CD36 deficiency reduces the size of atherosclerotic lesions in young and older ApoE knockout mice. Reducing the size of atherosclerotic lesions in ApoE deficient mice can also be apparently obtained by using a ligand (EP80317) derived from the growth hormone-releasing peptide family that also blocks the OxLDL binding site of CD36. Indeed, recent data by Marleau et al. showed that injection of EP80317, in ApoE deficient mice fed with an atherogenic diet, induced a significant reduction (up to 51%) of the lesion areas compared to not treated animals [45].

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4 Two congenic strains of mice and different roles for CD36

Another stream of data on CD36, recently obtained by Moore et al., contradicts in essence those obtained by Febbraio et al., by observing that the loss of CD36 in ApoE−/− mice does not reduce, and may even increase, the size of atherosclerotic lesions at the aortic valve level [46]. These researchers reported a reduction in peritoneal macrophage lipid accumulation coupled to significantly higher (40%) plasma cholesterol levels in male, but not female, CD36−/−ApoE−/− mice in comparison to ApoE−/−. According to Moore et al., uptake and endocytosis of OxLDL seem to be independent on scavenger receptors such as CD36. How can one reconcile such differences, between two sets of robust and interesting but opposing results, concerning the role of CD36 in atherosclerotic lesions? They are both right as indicated by Joseph L. Witztum [47]. However, several questions can be raised, in such a complex situation, to try and understand the results obtained by both groups.

Backcrossed CD36 ApoE deficient animals were 96.9% congenic with C57BL/6, for Febbraio et al., and 99% for Moore et al. The first question would be to ask if both groups are working on the same congenic strain of mice. A genome scan using single nucleotide polymorphisms (SNP) markers would rapidly give an answer to that question and ensure that the work is done on the same animal model. Statistically a congenic strain is thought, but that is not always the case, after 10 successive backcrossings taking between 2.5 to 3 years, to be 99.9% identical at all loci to the inbred strain with the exception of areas that are related to the investigated genes [48]. Animals that are not completely backcrossed, as pointed out by Moore et al., can lead to confounding results [49,50]. Indeed, it is possible that very slight variations of the investigated congenic strain, such as the number of backcrossing, may lead for example to alterations of the endothelial, macrophages or lipid functions.

A second question concerns the potential presence of pathogens in breeding rodent colonies [51]. Moreover, the size of lesions in ApoE deficient mice is increased by pathogens such as Chlamydia pneumoniae and Cytomegalovirus [52]. It is conceivable that differences between the 2 groups could be due to the presence of bacterial pathogens in ApoE−/− CD36−/− mice that could greatly exacerbate the size of lesions and neutralize the protective effects of CD36 deficiency. One should also note that CD36−/− mice have greatly reduced capacity to clear a pathogen such as S. aureus and its component lipoteichoic acid [53]. Embryo rederivation and maintenance with a specific and opportunistic pathogen-free (SOPF) status is the only way to ensure that results in these knockout animals are not affected by pathogens or parasites. Neither group mentions the use of such embryo rederivation and maintenance in a SOPF status in an atherosclerotic model that could be greatly affected by pathogens.

A third question is the value of lesions measurements over one time point and in limited areas of lesions. Indeed, atherosclerotic lesions size rapidly evolves in ApoE deficient mice, going from a fibro fatty to a fibrotic and/or calcified state, over 4 to 35 weeks [54]. These plaques may evolve at different speeds at various vascular sites prone to lesions (e.g. aortic arch and valves, descending aortic tree, and brachiocephalic arteries). Moore et al. have focused their work on a one time measurement of animals at 8 weeks and show differing results between males and females for the size of lesions at the level of the aortic arch, but not the aortic valve. Febbraio et al. measure aortic arch lesions at 12 and 35 weeks. Measurements of lesions at different sites over different period of time are expensive to perform but appear to be necessary to understand the role of a scavenger receptor such as CD36 in lesion formation.

The size of lesions in investigated mice are usually measured after staining with hematoxylin–eosin and oil red O and computer assisted image analysis. However, while giving the size of lesions, it does not give any information on the plaque biology or phenotype. Indeed, a fourth question deals with the possible effects of CD36 deficiency on macrophage and/or endothelial cells as well as other vascular cell phenotype. Transcriptomic and immunohistochemical markers should be used to indicate potential changes in the atherosclerotic lesions phenotype in CD36−/− ApoE−/− versus ApoE−/− mice with a C57BL6 background. Immunohistochemical and transcriptomic results show that endothelial cell adhesion molecules in ApoE mice significantly change their expression as the plaque matures from a fibro fatty to a fibrotic state [55,56]. Such type of data can effectively be used to investigate the effects of CD36 deletion on vessel wall and plaque phenotype.

A great number of areas, as seen from the above questions, still need to be clarified in order to fully understand differences between these 2 studies on the effects of CD36 deletion on atherosclerotic lesions. However, it is of interest to note that the formation and perpetuation of lesion system looks much more complex than originally thought. Indeed, disruption of chemokine CXCL16 (also recently described as a scavenger receptor called SR-PSOX) in ApoE−/− mice is associated with accelerated atherosclerosis despite macrophages being unable to bind and internalize OxLDL and still being recruited in large numbers to the aortic arch [57]. Similarly, in a transgenic murine model in which NFκB was inhibited, an observed reduction in foam cell formation was surprisingly associated with an increase in CD36 expression [58]. Moreover, it was recently shown that foam cell formation could be mediated by an endocytic pathway for native LDL called macropinocytosis that does not require the use of any specific scavenger receptors [59]. Absence of one or more scavenger receptors, such as CD36 or SRA, may involve other backup systems not previously implicated that could be potentially triggered by a deletion of a gene in ApoE−/− mice.

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5 CD36 and inflammation

Chronic inflammation is a major feature of human atherosclerosis and underlies development of the disease. A variety of pro- and anti-inflammatory cytokines are expressed in the atherosclerotic plaque, several of which modulate CD36 expression in an in vitro system and probably would act similarly under in vivo conditions. Treatment of peripheral blood mononuclear cells (PBMC) with macrophage colony-stimulating factor (MCSF) induces respectively a 7-fold increase in CD36 mRNA and a 2-fold increase in surface protein expression [60]. Moreover, Huh et al. found that monocyte CD36 surface expression increased upon tethering to HUVEC pre-treated with TNF-α [61]. Another pro-inflammatory cytokine secreted, within atherosclerotic lesions, by TH1 cells is IFN-γ. This cytokine was previously demonstrated by 2 groups to have pro-atherogenic properties [62,63] and yet Nakagawa et al. found that IFN-γ induced a reduction of CD36 expression in macrophages [64]. Treatment of THP-1 cells, a monocytic cell line, and isolated peripheral blood monocytes with IL-10 suppressed PPARγ-stimulated up-regulation of CD36 through reduced PPARγ expression and increased the expression of cholesterol efflux proteins ABCA1 and ABCG1 [65]. IL-10 is a potent anti-inflammatory cytokine produced primarily by monocytes and to a lesser extent by lymphocytes in atherosclerotic lesions [66]. IL-4 is another anti-inflammatory cytokine secreted by TH2 cells postulated to play a role in atherosclerosis given that it was found to be expressed in the lesions of hypercholesterolemic ApoE−/− mice [67]. Indeed, treatment of PBMC with IL-4 induced an approximate 4-fold increase in CD36 mRNA and 8- to 10-fold increase in CD36 protein expression [60]. It is also important to appreciate that ligation of OxLDL by CD36 induces activation of NFκB and the production of inflammatory cytokines [37], which could add to local inflammation when occurring in macrophages in atherosclerotic plaques.

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6 Hyperglycemia, CD36 and atherosclerosis

Hyperglycemia is a well-known risk factor for atherosclerosis and the relationships between CD36 and glucose or glucose derived products was closely investigated. Moreover CD36 has also been described to be a receptor for AGE [15]. Treatment of monocyte-derived-macrophages with either glucose or AGE resulted in an enhanced expression of CD36 [68,69]. CD36 expression was also observed to be increased in endarterectomy lesions from patients with a history of hyperglycemia [68], and also in monocytes from patients with type 2 diabetes [70]. Finally, Handberg et al., showed for the first time the presence of soluble CD36 (sCD36) in the plasma of type 2 diabetic patients, suggesting that sCD36 might represent a novel marker of IR [71]. Obese ob/ob mice (deficient in leptin), commonly used as a model of insulin-resistance and diabetes, showed an increase of CD36 expression, which could be linked to defective insulin signaling [72]. In contrast, the spontaneous hypertensive rat (SHR), used as a model for metabolic syndrome, displaying a variety of glucose- and fatty-acid-associated abnormalities, was reported to be deficient in CD36 [73]. Moreover, in a recent study, the same authors provided direct evidence that CD36 deficiency could promote defective insulin action and disordered fatty-acid metabolism in spontaneous hypertension. Indeed transgenic expression of wild-type CD36 in this model of hypertensive rat led to an improvement in insulin sensitivity [74].

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7 CD36 as a potential therapeutic target

Extensive evidences point to a significant role of CD36 in atherosclerotic lesions and suggest that it could be a lead target for therapeutic treatment. However, great caution has to be taken in promoting CD36 as a lead target in view of reports implicating it with disorders in fatty-acid metabolism. A number of drugs, as indicated below, either reduce or increase CD36 expression and it suggest that further work is needed to fully understand the implications on atherosclerosis and its clinical complications. CD36 may turn out to be a good expression marker for the evolution of atherosclerotic lesions or potentially the state of type 2 diabetic patients by assaying its level in plasma. Statins (or HMG-CoA reductase inhibitors) are a group of synthetic compounds used to lower the level of circulating cholesterol. The pleiotropic effects of Statins go well beyond their effects on lipoproteins and increasing evidences show their role as anti-inflammatory agents [75]. Pitavastatin treatment was found to reduce CD36 mRNA and surface protein expression in murine J774 macrophages and peritoneal macrophages as well as in THP-1 cells [76]. In the latter case, CD36 reduction was coincident with decreased PPARγ activity. Similarly, administration of atorvastatin to hypercholesterolaemic patients led, after 6 days, to a significant reduction in platelet CD36 expression [77]. Fuhrman et al. examined the consequence of atorvastatin treatment on cellular uptake of OxLDL [78]. Monocyte-derived-macrophages obtained from hypercholesterolemic patients following atorvastatin therapy took up a significantly lower amount of OxLDL and up-regulated CD36 to a lesser degree than monocyte-derived-macrophages obtained from the same individuals prior to treatment. Aspirin, commonly used as a platelet inhibitor drug and anti-inflammatory, was also reported to affect CD36 regulation. Indeed, at therapeutic plasma concentration, aspirin increased CD36 expression in human monocyte-derived-macrophages. This induction was proven to be prostaglandin E2 (PGE2) dependent and PPARγ independent [79]. Finally, anti-protease inhibitors (Ritonavir) in HIV treatment have shown to significantly increase CD36 expression in circulating monocytes and PBMC and be associated to hypercholesterolemia, hypertriglycemia and type 2 diabetes [31,80,81].

Unsaturated fatty-acids and their oxidation products are also observed to modulate CD36 gene expression in human macrophages. The active molecules of fish-oil n-3 fatty-acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are thought to partially protect against cardiovascular diseases. However the mechanisms by which fish-oils confer their benefits are not fully understood. Pietsch et al. demonstrated that EPA and DHA treatment in human monocytic cells resulted in a significant reduction of CD36 expression at both mRNA and protein levels [82]. In contrast, Vlallve et al. observed that acid EPA, DHA and to a lesser extent oleic and linoleic acids significantly enhanced CD36 expression in THP-1 and monocyte-derived-macrophages both at the transcriptomic and protein levels. However, a significant reduction in CD36 expression was noted with oxidation products (aldehydes) of fatty-acids such as 4-hydroxynonenal (HNE) and hexanal, 2,4-decadienal (DDE) [83].

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8 Conclusions

This review focuses on the role of CD36 in atherosclerosis and related inflammatory diseases. However, the role of this scavenger receptor is not restricted to vascular lesions and it is implicated in neutrophil phagocytosis by macrophages as well as a large number of other cellular functions. As a fatty-acids receptor, it has been shown to be implicated in obesity and that it could determine our desire for dietary fats [84], by being involved in the oral long chain fatty-acids detection [85]. CD36 has also been implicated in the inhibition and regression of the inflammatory corneal neovascularization [86]. A reduction of CD36 expression has also been observed in leukocytes from patients with Alzheimer disease as a disease-related phenomenon [87]. CD36 was also reported to be a sensor of microbial diacylglycerides in cooperation with TLR2/6 heterodimer [88].

Until recently, it was clear that this scavenger receptor (CD36) had a real implication in atherosclerotic lesion development, and also in risk factors associated to the disease. However, Moore and other authors brought new insights on the subject and launched the debate on whether or not CD36 is a key component for atherosclerosis. As we mentioned earlier, there is robust evidence in the mouse that CD36 and/or SRA are the main macrophage receptors for OxLDL. However it is clear that there are many alternative scavenger receptors, and it is easy to envisage that others could take over the function under particular conditions, or that second signals, e.g. from bacterial products, could render CD36 non-essential, particularly in its cell signaling role. The data generated from knockout murine models on the role of macrophage scavenger receptors CD36 or SRA need to be taken with some caution. Indeed, deletion of one or more genes to investigate their functions in an atherosclerotic mice model is turning more complex than anticipated. Several key issues need to be reviewed to ensure that researchers are working on the same animal model and that this model is representative of the disease to be investigated. It is clear that genome scan and SOFP status of knockout mice need to be systematically performed and indicated in such complex and delicate studies. Moreover, furthermore work in other species is required before the significance of the findings to man can be assessed.

The ApoE−/− atherosclerotic murine model is widely different from the disease observed in man with none of the clinical end points such as plaque rupture and thrombotic ischemia. Hence, answers to the functional role of CD36 in atherosclerosis most probably need to come from clinical studies performed on man. Clinical observations on individuals with CD36 deficiency, which is present for example in about 3% of the Japanese population, have started to give some insights on this scavenger receptor [41]. These CD36 deficiencies, due to several identified mutations, reduce the OxLDL uptake by macrophages by 50%. Although anti-atherosclerotic benefits might be anticipated, no clinical evidence has so far been reported [89]. However, a number of these CD36-deficient individuals show hypertension, hyperlipidemia and mild elevation of fasting glucose levels. In one study, but not in others, CD36 deficiency is associated with a higher frequency of patients with coronary heart diseases [90].

All together investigations performed on individuals deficient in CD36 appear to be at an early stage and suggest that further work is very much needed on isolated monocytes/macrophages in tandem with imaging techniques to assess progression of atherosclerosis. Work on isolated monocytes/macrophages could indicate if the absence of a major scavenger receptor, such as CD36, affects signaling pathways or the expression of important surface receptors. Moreover, carotid intima/media thickness measurement in CD36-deficient individuals compared to age and sex controls could over a short period of time indicate if CD36 deficiency is protective in the initiation and perpetuation of atherosclerotic lesions.

  1. Sophie Collot-Teixeiraa,b,*,
  2. Juliette Martina,b,
  3. Chris McDermott-Roeb,
  4. Robin Postona and
  5. John Louis McGregora,b,c
  1. a Cardiovascular Division, King's College, London, UK
  2. b Thrombosis Research Institute, London, UK
  3. c INSERM Unit 689, Hôpital Lariboisière, Paris, France
  1. * Corresponding author. Cardiovascular Division, King's College London, Waterloo Campus, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. Tel.: +44 20 7848 4281; fax: +44 20 7848 3743. sophie.collot{at}kcl.ac.uk
  • Received October 30, 2006.
  • Revision requested March 2, 2007.
  • Accepted March 9, 2007.
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Acknowledgements

Sophie Collot-Teixeira is supported by a Grant from the British Heart Foundation (PG/05/090). Juliette Martin and Chris McDermott-Roe were supported by the Garfield Weston Foundation through a Grant to the Genomics & Atherothrombosis Laboratory, Thrombosis Research Institute, London, UK. J.L. McGregor is grateful to INSERM and particularly to Prof. Bernard Levy, Director of INSERM U689 for his constant help and support.

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  1. Cardiovasc Res (2007) 75 (3): 468-477. doi: 10.1016/j.cardiores.2007.03.010
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