UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidence strongly implicates oxidized LDL (Ox-LDL) in the pathogenesis of atherosclerosis. Several receptors have been identified that bind and internalize Ox-LDL, but their relative importance in vivo is unclear. CD36 is an 88-kD transmembrane glycoprotein expressed on monocytes/macrophages, platelets, and microvascular endothelium that has been implicated as a putative receptor for Ox-LDL. We demonstrate that an anti-CD36 monoclonal antibody inhibited 50% of the specific binding and 26% of the specific degradation of Ox-LDL by human monocyte-derived macrophages. To characterize more completely this binding we evaluated interactions between CD36 and Ox-LDL in murine NIH-3T3 cells stably transfected with human CD36 cDNA. Ox-LDL bound to CD36-transfected 3T3 cells in a saturable manner. Specific binding, internalization, and degradation of Ox-LDL were increased fourfold in CD36-transfected cell lines compared with 3T3 cells transfected with vector alone. Binding of Ox-LDL to CD36-transfected 3T3 cells was inhibited by a panel of anti-CD36 antibodies and by soluble CD36 but not by thrombospondin. Specificity of binding was demonstrated by the equivalent binding of LDL and acetylated LDL to control and CD36-transfected 3T3 cells. The epitope or epitopes on Ox-LDL recognized by CD36 are undefined. Two observations suggest that CD36 recognizes a lipid moiety or that the lipid portion of the lipoprotein is essential for apoprotein recognition. The first is that the increased binding of Ox-LDL to CD36-transfected 3T3 cells is abrogated by delipidation of the lipoprotein, and the second is that oleic acid competes for the binding of Ox-LDL to CD36-transfected 3T3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidized LDL binds to CD36 on human monocyte-derived macrophages and transfected cell lines. Evidence implicating the lipid moiety of the lipoprotein as the binding site. 753 25

CD36, a multifunctional adhesion receptor e.g. for thrombospondin and collagen, as well as a scavenger receptor for oxidized low density lipoprotein, is expressed e.g. on platelets and monocytes. By this dual role it might be involved in early steps of atherosclerosis like the recruitment of monocytes and formation of foam cells. We therefore studied the effects of n-3 fatty acids on CD36 expression in human monocytic cells. Incorporation of eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) into cellular phospholipids resulted in a significant reduction of CD36 expression at the mRNA and protein level, whereas arachidonic acid (AA, C20: 4n-6) and linoleic acid (LA, C18:2n-6) tended to increase CD36 expression compared to the control. This specific down-regulation of CD36 by n-3 fatty acids in cells involved in the initiation and progression of atherogenesis and inflammation, represents a further mechanism that may contribute to the beneficial effects of n-3 polyunsaturated fatty acids (PUFA) in these disorders.
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PMID:N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. 755

The thrombospondin and collagen receptor CD36 was recently found to function, also, as a dominating scavenger receptor for oxidized low-density lipoproteins (oxLDL). Thus, CD36 might be a key factor in monocyte adhesion and foam cell formation. We, therefore, studied CD36 expression in monocytic cells under conditions of cholesterol depletion and overload. Human monocytic U937 cells were cultured under control conditions and in the presence of lovastatin, native, and oxLDL. The expression of lipoprotein receptors was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescence-activated cell sorting (FACS). In sharp contrast to the feedback-controlled ApoB100 specific receptor for native low-density lipoprotein (LDL-R), CD36 expression was significantly reduced by lovastatin in a dose-dependent manner, both at the RNA and protein level, resulting in decreased cellular oxLDL binding. The addition of mevalonate completely reversed lovastatin effects, whereas excess LDL was only partially effective. Similarly to native LDL, oxLDL reduced LDL-R transcription, but did not affect CD36 transcription. CD36 protein surface expression fell, however, due to internalization of CD36 loaded with oxLDL. In summary, monocytic expression of CD36, in contrast to the native LDL-R, is reduced by cholesterol synthesis inhibition and not by feedback inhibition from substrate overexposure. CD36 suppression is a new pharmacological action of lovastatin that may contribute to its clinical benefit by attenuating monocyte adhesion and foam cell formation, key steps in atherosclerosis.
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PMID:Lovastatin reduces expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. 868 97

Membership in the broad family of scavenger receptors has grown significantly. Two new scavenger receptor receptors have been cloned (SR-BI and SR-CI) and a previously isolated integral membrane protein (CD36) has been found to possess lipoprotein binding properties that entitle it to be included in the family. The breadth of ligand recognition of this class of receptors has also increased with the discovery that high-density lipoproteins and anionic phospholipids can bind to scavenger receptors. New studies linking these receptors to apoptotic and signal transduction pathways have further enlarged their potential contributions to normal immune function as well as the process of atherosclerosis. Clarifying the physiologic as well as pathophysiologic significance of these multifunctional proteins has proven challenging, but mouse homologous recombination technology will soon yield critical insights into the role scavenger receptors play in atherosclerosis and other macrophage-associated immune functions.
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PMID:Scavenger receptors in atherosclerosis. 905 Mar 78

Oxidation of low density lipoproteins (LDL) has been implicated as a causal factor in the pathogenesis of atherosclerosis. Oxidized LDL has been found to exhibit numerous potentially atherogenic properties in vitro, including receptor-mediated uptake by macrophages. Oxidized LDL is a ligand for the class A scavenger receptor type I/II (SR-AI/II), but cross-competition studies with cultured macrophages suggested that there is an additional receptor(s) that is specific for oxidized LDL and that does not interact with acetyl LDL or other chemically modified LDL. A number of macrophage membrane proteins, including CD36, FcgammaRII-B2, scavenger receptor BI, and macrosialin/CD68, have been found to bind to oxidized LDL in vitro and have been proposed as candidate oxidized LDL receptors. However, because of overlapping ligand specificity with the SR-AI/II, it has been difficult to evaluate the relative importance of these proteins in the uptake of oxidized LDL by macrophages. In the present report, we have studied the uptake and degradation of oxidized LDL by macrophages from mice in which the SR-AI/II gene had been disrupted. The uptake of acetyl LDL was reduced by more than 80% in macrophages from scavenger receptor knockout mice, confirming that most of the uptake of acetyl LDL by macrophages can be attributed to this receptor. In contrast, the uptake of extensively oxidized LDL was reduced by only 30% and showed high affinity, saturable uptake with apparent Km of about 5 microg/ml, similar to that of the SR-AI/II. This indicates that about 70% of the uptake of oxidized LDL in macrophages is attributable to an alternate oxidized LDL receptor(s). In contrast to findings reported with CD36, mildly oxidized LDL was internalized much more slowly than extensively oxidized LDL. Unlabeled oxidized LDL, polyinosinic acid, phosphatidylserine-rich liposomes, and LDL or bovine albumin modified by fatty acid oxidation products were effective competitors for the uptake of radioiodinated oxidized LDL by macrophages from knockout mice, whereas acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors. This ligand specificity differs from that of CD36-related (class B) scavenger receptors but is similar to the reported specificity of macrosialin/CD68 in ligand blots. However, the rate of uptake of oxidized LDL by knockout macrophages was not increased by phorbol ester or in thioglycollate-elicited macrophages, both of which are expected to increase the amount of macrosialin on the cell surface. In macrophages from SR-AI/II knockout mice, ligand blots of membrane proteins with iodinated, oxidized, or acetylated LDL revealed several bands, with apparent molecular size on SDS-polyacrylamide gel electrophoresis of 60, 94, 124, and 210 kDa, but none of the bands were specific for oxidized LDL. These results provide direct evidence that a receptor other than SR-AI/II is responsible for most of the uptake of oxidized LDL in murine macrophages, but further studies are needed to identify the receptor(s) involved.
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PMID:High affinity saturable uptake of oxidized low density lipoprotein by macrophages from mice lacking the scavenger receptor class A type I/II. 914 99

The uptake of oxidized low density lipoprotein (OxLDL) by macrophages is a key event implicated in the initiation and development of atherosclerotic lesions. Two macrophage surface receptors, CD36 (a class B scavenger receptor) and the macrophage scavenger receptor (a class A scavenger receptor), have been identified as the major receptors that bind and internalize OxLDL. Expression of CD36 in monocyte/macrophages in tissue culture is dependent both on the differentiation state as well as exposure to soluble mediators (cytokines and growth factors). The regulatory mechanisms of this receptor in vivo are undetermined as is the role of lipoproteins themselves in modulating CD36 expression. We studied the effect of lipoproteins, native LDL and modified LDL (acetylated LDL (AcLDL) and OxLDL) on the expression of CD36 in J774 cells, a murine macrophage cell line. Exposure to lipoproteins resulted in a marked induction of CD36 mRNA expression (4-8-fold). Time course studies showed that maximum induction was observed 2 h after treatment with AcLDL and at 4 h with LDL and OxLDL. Increased expression of CD36 mRNA persisted for 24 h with each treatment group. Induction of CD36 mRNA expression was paralleled by an increase in CD36 protein as determined by Western blot with the greatest induction by OxLDL (4-fold). In the presence of actinomycin D, treatment of macrophages with LDL, AcLDL, or OxLDL did not affect CD36 mRNA stability, implying that CD36 mRNA was transcriptionally regulated by lipoproteins. To determine the mechanism(s) by which lipoproteins increased expression of CD36 we evaluated the effects of lipoprotein components on CD36 mRNA expression. ApoB 100 increased CD36 mRNA expression significantly, whereas phospholipid/cholesterol liposomes had less effect. Incubation of macrophages with bovine serum albumin or HDL reduced expression of CD36 mRNA in a dose-dependent manner. Finally, to evaluate the in vivo relevance of the induction of CD36 mRNA expression by lipoproteins, peritoneal macrophages were isolated from mice following intraperitoneal injection of lipoproteins. Macrophage expression of CD36 mRNA was significantly increased by LDL, AcLDL, or OxLDL in relation to mice infused with phosphate-buffered saline, with OxLDL causing the greatest induction (8-fold). This is the first demonstration that exposure to free and esterified lipids augments functional expression of the class B scavenger receptor, CD36. These data imply that lipoproteins can further contribute to foam cell development in atherosclerosis by up-regulating a major OxLDL receptor.
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PMID:Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. 926 Nov 89

Angiotensin II (Ang-II) has been shown to possess several atherogenic properties including its ability to induce macrophage-mediated oxidation of LDL and to form Ang-II-modified LDL which is taken up by macrophages at enhanced rate. Oxidized-LDL (Ox-LDL) is also taken up by macrophages at enhanced rate via several scavenger receptors, leading to macrophage cholesterol accumulation. In the present study we examined the effect of Ang-II on the uptake of Ox-LDL by peritoneal macrophages derived from Balb/c mice (MPM). Intraperitoneal injection of Ang-II (10(-7) M, once daily for a period of 2 days) to the mice resulted in an increased Ox-LDL uptake up to 60%, in comparison to macrophages from placebo-treated mice. Similar results were obtained when Ang-II (10(-7) M) was injected to the mice twice a week for a period of three months. This Ox-LDL uptake was Ang-II dose-dependent. The cellular uptake of acetylated-LDL (Ac-LDL), another ligand for scavenger receptors, however, was not affected by Ang-II injection to the mice. Furthermore, preincubation of the MPM with the monoclonal antibody, anti CD36, reduced macrophage uptake of Ox-LDL in Ang-II-treated mice by only 11%. Ang-II administration to mice resulted in a 60% increase in the macrophage cellular proteoglycan content. Chondroitinase treatment of MPM decreased Ox-LDL cellular uptake by 20% and by 38% in placebo-treated and Ang-II-treated cells, respectively. We thus conclude that Ang-II administration to mice enhances their macrophage Ox-LDL uptake via its stimulating effect on cellular proteoglycan content and this process can lead to foam cell formation and atherosclerosis.
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PMID:Angiotensin II injection into mice increases the uptake of oxidized LDL by their macrophages via a proteoglycan-mediated pathway. 934 70

Mouse and hamster SR-BI glycoproteins and their putative human counterpart CLA-I are so far the only scavenger receptors known to bind both native and modified lipoproteins. CD36, a multigland glycoprotein structurally related to SR-BI and CLA-1, has been reported to bind oxidized low density lipoprotein (OxLDL) and acetylated LDL (AcLDL). In this report, we have studied the ability of CD36 to bind native lipoproteins. By transient expression of human CD36 in mammalian and insect cells, we demonstrate that CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, VLDL, and, as previously reported, for OxLDL and AcLDL. The specificity of these interactions is supported by the dose-dependent inhibiton, effect of a monoclonal antibody against CD36. Furthermore, at least for HDL, binding to CD36 does not require the presence of apoE. These findings, together with preferential expression of CD36 in tissues performing very active fatty acid metabolism (skeletal muscle, heart, mammary epithelium, and adipose tissue) and its involvement in foam cell formation (macrophages), suggest that binding of lipoproteins to CD36 might contribute to the regulation of lipid metabolism, and to the pathogenesis of atherosclerosis.
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PMID:Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. 955 43

To clarify the role of type I and type II macrophage scavenger receptors (MSR-A) in the progression of diet-induced atherosclerosis, we generated mice lacking both MSR-A and low-density lipoprotein receptor (LDLR). After 4 or 12 weeks of a high-fat diet, the sizes of atherosclerotic lesions in MSR-A/LDLR double knockout mice were significantly reduced (p < 0.05) compared with those in LDLR single knockout mice. However, atherosclerotic lesions mainly composed of foamy macrophages were still observed in double knockout mice. Formation of atherosclerotic lesions in double knockout mice was partially explained by the participation of scavenger receptors other than MSR-A such as MARCO, CD36, and macrosialin/CD68. These receptors were clearly demonstrated in the atherosclerotic lesions in double knockout mice as well as LDLR single knockout mice by immunohistochemistry or by reverse transcriptase-polymerase chain reaction. Because the very low density lipoprotein (VLDL) fraction was elevated in the double and single knockout mice, we further examined the possibility that VLDL may participate in foam cell formation in atherosclerotic lesions. When incubated with VLDL isolated from LDLR-deficient mice, cholesterol ester accumulation and foamy transformation occurred in MSR-A-deficient macrophages as well as in normal macrophages. These data indicate that MSR-A plays an essential role in the development of diet-induced atherosclerosis. It also appears that other scavenger receptors, such as MARCO, CD36, and macrosialin/CD68, as well as uptake of VLDL are involved in foam cell formation during atherogenesis in MSR-A/LDLR double knockout mice.
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PMID:Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice. 956 87

CD36, also known as GPIIIb or GPIV, is a main protein of the platelet membrane. Accumulating evidence implicates CD36 in the pathogenesis of atherosclerosis. CD36 binds to cholesteryl-hemisuccinate coupled to agarose. This binding may be of physiologic relevance since CD36 has a long extracellular hydrophobic region at its N-terminus and belongs to a family of proteins involved in lipid metabolism. This newly discovered binding property of CD36 was used to develop a rapid, efficient and gentle two-step purification method for CD36 from human platelets.
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PMID:Human platelet CD36 (GPIIIb, GPIV) binds to cholesteryl-hemisuccinate and can be purified by a simple two-step method making use of this property. 960 40

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