Recombinant CD36 inhibits oxLDL-induced ICAM-1-dependent monocyte adhesion

Stewart, Bradford W.; Nagarajan, Shanmugam

doi:10.1016/j.molimm.2005.02.007

Cited by 26 publications

(26 citation statements)

References 48 publications

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“…Another approach is to specifically inhibit pathological ligands for CD36. Previously, a recombinant, soluble form of CD36 was shown to compete for the binding of oxLDL to membrane-expressed CD36 and to prevent oxLDL-induced adhesion of monocytes to endothelial cells (33). In this study, a short synthetic peptide representing the identified binding domain inhibited biological activity of oxPC CD36 and oxidized LDL in macrophage foam cell assays and in a platelet activation assays.…”

Section: Discussionmentioning

confidence: 73%

Mapping and Characterization of the Binding Site for Specific Oxidized Phospholipids and Oxidized Low Density Lipoprotein of Scavenger Receptor CD36

Kar

Ashraf

Valiyaveettil

et al. 2008

Journal of Biological Chemistry

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Recent studies have identified a novel family of oxidized phosphatidylcholines (oxPC CD36 ) that serve as highly specific ligands for scavenger receptor CD36. oxPC CD36 accumulate in vivo and mediate macrophage foam cell formation as well as promote platelet hyper-reactivity in hyperlipidemia via CD36. The structural basis of oxPC CD36 binding to CD36 has not been elucidated. We used liquid-phase binding to glutathione S-transferase fusion proteins containing various regions of CD36 to initially identify the region spanning CD36 amino acids 157-171 to contain a major binding site for oxPC CD36 CD36 is a 472-amino-acid, 88-kDa heavily glycosylated transmembrane protein that is expressed in various cell types including macrophages, platelets, microvascular endothelial cells, and adipocytes (1, 2). CD36 has been shown to play a significant role in a number of physiological and pathological processes in vivo including atherogenesis, lipid sensing and metabolism, innate immune responses, angiogenesis, uptake of apoptotic cells, and diabetes (2-4). CD36 involvement in such a variety of processes can be partially explained by its capacity to recognize a number of various distinct ligands. Examples of CD36 ligands include thrombospondin-1 (5), oxidized low density lipoproteins (oxLDL) 2 (6), oxidized phospholipids (7-9), fatty acids (10), microbial diacylglycerides (4), hexarelin (3), collagen (11), and malarial parasite-infected erythrocytes (12).That CD36 can function as a multiligand receptor is conceivable assuming that it has multiple ligand binding domains. Several studies suggest, for example, that the binding sites of thrombospondin-1 and oxLDL on CD36 are different (13,14). Two distinct binding sites are proposed for oxLDL on CD36. Studies using a monoclonal antibody have shown that domain 155-183 of CD36 plays a critical role in the binding of LDL oxidized by copper (15). Solid phase binding assays using recombinant fusion proteins spanning various regions of CD36, however, implicate the domain 28 -93 as the major binding site for oxLDL (16).We have recently identified a novel family of oxidized choline glycerophospholipids (oxPC CD36 ) that mediate CD36-dependent recognition of LDL oxidized by various pathways. The structural aspect of oxPC CD36 essential for high affinity binding to CD36 is an sn-2 acyl group that incorporates a terminal ␥-hydroxy(or oxo)-␣,␤-unsaturated carbonyl. A characteristic feature of oxPC CD36 conformation is a negatively charged distal end of the sn-2 acyl chain residue that partitions into the aqueous phase (17). oxPC CD36 are formed during the oxidation of LDL by multiple distinct pathways, serve as specific high affinity ligands for CD36 (9), and are present in vivo at sites of enhanced oxidative stress (18 -20). OxPC CD36 mediate foam cell formation induced by oxidized LDL via macrophage CD36 and induce a prothrombotic phenotype in hyperlipidemia via platelet CD36 (18,20).In this current study, we investigated the structural basis for the recognition of oxPC CD36 by CD36 using...

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Section: Discussionmentioning

confidence: 73%

Mapping and Characterization of the Binding Site for Specific Oxidized Phospholipids and Oxidized Low Density Lipoprotein of Scavenger Receptor CD36

Kar

Ashraf

Valiyaveettil

et al. 2008

Journal of Biological Chemistry

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“…Finally, in vitro studies show that ox-LDL induces dosedependent expression of ICAM-1 on endothelial cells and stimulates ICAM-1-dependent adhesion of monocytes [21,22]. Together, these data suggest that the oxidative modification of LDL and expression of ICAM-1 may be causally linked to the aetiology of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 79%

Circulating oxidised low-density lipoprotein and intercellular adhesion molecule-1 and risk of type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study

et al. 2006

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Aims/hypothesis To evaluate the role of oxidative stress and inflammation in the aetiology of type 2 diabetes, we examined the association of oxidised LDL (ox-LDL) and soluble intercellular adhesion molecule-1 (sICAM-1) levels with type 2 diabetes incidence over 9 years in the Atherosclerosis Risk in Communities Study. Materials and methods In a large, prospective, case-cohort design, ox-LDL and sICAM-1 were measured in stored plasma samples collected at baseline in stratified samples of 581 diabetes cases and 572 non-cases selected from 10,275 middle-aged men and women without prevalent diabetes at baseline. Results Compared with non-cases, diabetes cases had significantly higher mean baseline levels of ox-LDL and sICAM-1. Elevated ox-LDL and sICAM-1 were both associated with increased risk of incident diabetes after adjustment for age, sex, race and centre, with hazard ratios for the highest vs lowest tertiles of 1.68 (95% CI 1.25-2.24) and 1.91 (95% CI 1.45-2.50), respectively. After additional adjustment for fasting glucose, waist circumference, HDL-cholesterol, triacylglycerol, hypertension and C-reactive protein, only sICAM-1 remained an independent predictor of incident diabetes (hazard ratio 1.50; 95% CI 1.02-2.23). Conclusions/interpretation In this community-based cohort of middle-aged US adults, elevated plasma ox-LDL and sICAM-1 levels were associated with increased risk of type 2 diabetes. Measurement of ICAM-1 or ox-LDL, or other measures related to inflammation or oxidative stress, may be helpful in identifying those patient populations in which to test whether novel therapies that inhibit specific pathways related to inflammation or oxidative stress are beneficial in the prevention of diabetes in humans.

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“…In one approach, the extracellular domain of the oxLDL scavenger receptor CD36 was fused to the Fc domain of human IgG1 and the resulting chimeric sCD36-Ig was able to inhibit the adhesion of monocytes to oxLDL. 36 Likewise, recombinant Lox1-Fc fusion proteins were shown to inhibit binding and internalization of oxLDL by cell surface Lox-1, but only when the construct was oligomerized via a polyclonal antibody against Fc. 37 These approaches support the in vitro results of CD68-Fc 19 and point to one mode of action of soluble Fc fusion proteins, ie, impeding the binding of oxLDL to scavenger receptors and interfering with oxLDL uptake by monocytes and associated foam cell formation.…”

Section: Discussionmentioning

confidence: 99%

Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis

Zeibig

Wagner

et al. 2011

Circulation Research

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Rationale: There is strong evidence that oxidative modification of low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and that oxLDL may profoundly influence the mechanical stability of atherosclerotic plaques.Objective: To block oxLDL, we designed, expressed, and tested Fc-CD68, a soluble oxLDL binding protein consisting of human Fc and the extracellular domain of the human oxLDL-binding receptor CD68. Methods and Results:Fc-CD68 bound with high specific affinity to oxLDL and strongly bound and colocalized with oxLDL in plaques. To study the effects of repeated administrations of Fc-CD68 on the progression of atherosclerosis and plaque vulnerability, 12-and 16-week old cholesterol-fed ApoE ؊/؊ mice received either Fc-CD68 (n‫)6؍‬ or Fc control protein (n‫6؍‬ to 8) thrice weekly for 4 weeks. Macroscopic and histological analysis of Sudan red lipid staining showed strong and significant reduction of plaque extension in the aorta and in the aortic root, respectively. Histological analysis of pentachrome-and Sirius-stained sections of the brachiocephalic arteries of 20 week-old ApoE ؊/؊ mice revealed that Fc-CD68 significantly reduced the occurrence of spontaneous ruptures of established plaques by Ϸ20%, compared with Fc and drastically increased the collagen content of plaques. Furthermore, in immunostained sections of the brachiocephalic artery and the aortic root, Fc-CD68 reduced the infiltration of plaques with T lymphocytes, and macrophages by Ϸ50% and 30%, respectively. Key Words: oxLDL Ⅲ atherosclerosis Ⅲ Fc-CD68 Ⅲ soluble oxLDL binding protein O xidatively modified low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and contributes to the progression of atherosclerosis in various ways. 1,2 It can induce the transformation of macrophages into lipid-laden foam cells, 3,4 it is a chemotactic agent for monocytes, and it reduces the motility of macrophages which then become resident in the arterial intima. 5 In addition, oxLDL is recognized as foreign by the immune system. 6 oxLDL-specific T lymphocytes are present in the vessel wall where they are locally restimulated and further stimulate macrophages by cytokine release. 7,8 Furthermore, oxLDL is cytotoxic and damages the endothelium, 9 thereby favoring platelet adhesion. 10 In advanced atherosclerotic lesions, the cytotoxicity of oxLDL may even result in irreversible cell necrosis. 10,11 In addition to contributing to atherosclerosis, oxLDL may profoundly influence the mechanical stability of atherosclerotic plaques, because foam cells offer little mechanical stability and because activated macrophages may secrete factors that weaken plaques, ie, metalloproteinases. 12,13 Rupture of atherosclerotic plaques leads to vascular injury and subsequent myocardial infarction and stroke. Several studies have demonstrated conclusively that the morphology of the atherosclerotic plaques, rather than their size, is predictive for the frequency of plaque ruptures (summarized by Rekhter 14 ). The most relevant morphological characteris...

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Recombinant CD36 inhibits oxLDL-induced ICAM-1-dependent monocyte adhesion

Cited by 26 publications

References 48 publications

Mapping and Characterization of the Binding Site for Specific Oxidized Phospholipids and Oxidized Low Density Lipoprotein of Scavenger Receptor CD36

Mapping and Characterization of the Binding Site for Specific Oxidized Phospholipids and Oxidized Low Density Lipoprotein of Scavenger Receptor CD36

Circulating oxidised low-density lipoprotein and intercellular adhesion molecule-1 and risk of type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study

Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis

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