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At least 343 records · Page 19Linked to original sources
PubMed2002

Association of thrombospondin-1 with the actin cytoskeleton of human thrombin-activated platelets through an alphaIIbbeta3- or CD36-independent mechanism.

Thrombospondin-1 (TSP-1) is an adhesive glycoprotein which, when secreted from alpha-granules of activated platelets, can bind to the cell surface and participate in platelet aggregate formation. In this study, we show that thrombin activation leads to the rapid and specific association of a large amount of secreted alpha-granular TSP-1 with the actin cytoskeleton. This cytoskeletal association of TSP-1 was correlated with platelet secretion, but not aggregation, and was inhibited by cytochalasin D, an inhibitor of actin polymerization. Association of TSP-1 with the actin cytoskeleton was mediated by membrane receptors, as shown by using MAII, a TSP-1-specific monoclonal antibody that inhibited both TSP-1 surface binding to activated platelets and cytoskeletal association. TSP-1 and its potential membrane receptors, e.g. alphaIIbbeta3 integrin, CD36 and CD47, concomitantly associated with the actin cytoskeleton. However, studies on platelets from a patient with type I Glanzmann's thrombasthenia lacking alphaIIbbeta3 and another with barely detectable CD36 showed normal TSP-1 surface expression and association with the actin cytoskeleton. Likewise, no involvement of CD47 in TSP-1 association with the actin cytoskeleton could be inferred from experiments with control platelets using the function-blocking anti-CD47 antibody B6H12. Finally, assembly of signalling complexes, as observed through translocation of tyrosine-phosphorylated proteins and kinases to the actin cytoskeleton, was found to occur in concert with cytoskeletal association of TSP-1, in control platelets as well as in thrombasthenic and CD36-deficient platelets. Our results imply a role for the actin cytoskeleton in the membrane-surface expression process of TSP-1 molecules and suggest a possible coupling of TSP-1 receptors to signalling events occurring independently of alphaIIbbeta3 or CD36. These results provide new insights into the link between surface-bound TSP-1 and the contractile actin microfilament system which may promote platelet aggregate cohesion.

Actins↗
PubMed2002

The terminal six amino-acids of the carboxy cytoplasmic tail of CD36 contain a functional domain implicated in the binding and capture of oxidized low-density lipoprotein.

CD36, a major adhesion molecule expressed by monocytes/macrophages, plays a key role in the binding and internalization of oxidized low-density lipoprotein (OxLDL). This adhesion molecule, a member of an important scavenger receptor family, contains a very short C-terminal cytoplasmic tail that is known to induce intracellular signalling events. However, the domains on the cytoplasmic tail involved in such signal transduction are unknown. In this study, we have investigated the functional components of the cytoplasmic tail by site-directed mutagenesis coupled with functional OxLDL and monoclonal antibody (mAb) binding studies. Seven truncated or punctual CD36 constructs, localized in the cytoplasmic tail, were produced by site-directed mutagenesis. Each construct was stably expressed in HEK293 cells. We used a quantitative and a qualitative method, labelling OxLDL with either iodine or rhodamine, to determine the functional importance of the cytoplasmic domains in OxLDL internalization. Results indicate that: (1) a deletion of the last amino-acid (construct K472STOP) significantly reduces, compared with wild-type, the binding, internalization and degradation of OxLDL; (2) truncation of the last six amino-acids (construct R467STOP) significantly reduces OxLDL binding; (3) the above two constructs (K472STOP and R467STOP) showed a reduced rate of OxLDL internalization compared with wild-type; (4) the binding and rate of internalization of an anti-CD36 monoclonal antibody (10/5) was not affected by the above mentioned mutants (K472STOP and R467STOP), compared with wild-type. This study shows, for the first time, a specific site on the CD36 cytoplasmic tail that is critical for the binding, endocytosis and targeting of OxLDL.

Amino Acid Sequence↗
PubMed1996

Biochemical isolation of a membrane microdomain from resting platelets highly enriched in the plasma membrane glycoprotein CD36.

Here we describe the isolation and characterization of a Triton X-100-insoluble fraction isolated from lysates of platelets by flotation in sucrose gradients. Transmission electron microscopy of the insoluble material revealed a heterogeneous population of vesicles ranging in size from 20 to 1000 nm, and Western blot analyses of platelet lysates for the caveolae structural coat protein, caveolin/VIP21, were negative. Biochemical characterization of the Triton X-100-insoluble fraction showed it to be cholesterol-rich, greatly and specifically enriched in the plasma membrane glycoprotein CD36, and also to contain Src and the Src-related kinase, Lyn. CD36 within this fraction is shown to be palmitoylated, but the fraction itself is not generally enriched in palmitoylated platelet proteins. These results suggest that this fraction represents caveolin-negative, CD36-rich microdomains in the resting platelet membrane. CD36 can form associations with certain Src-related kinases and can signal to activate platelets. These results suggest the possibility that such microdomains are implicated in platelet activation.

Blood Platelets↗
PubMed1998

A recombinant peptide based on PfEMP-1 blocks and reverses adhesion of malaria-infected red blood cells to CD36 under flow.

During falciparum malaria infection, severe complications ensue because parasitized red blood cells (PRBCs) adhere to endothelial cells and accumulate in the microvasculature. At the molecular level, adhesion is mediated by interaction of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1) on the PRBC surface with receptors on the surface of endothelial cells, including CD36. We have shown that a recombinant 179-residue subfragment of PfEMP-1 (rC1-2[1-179]), which encompasses the CD36-binding region, inhibits and reverses adhesion of PRBCs to CD36 under physiologically relevant flow conditions. rC1-2[1-179] inhibited adhesion in a concentration-dependent manner over the range 100 pM to 2 microM, with up to 99% of adhesion blocked at the highest concentration tested. The antiadhesive activity of rC1-2[1-179] was not strain specific and almost totally ablated adhesion of four different parasite lines. Furthermore, rC1-2[1-179] showed remarkable ability to progressively reverse adhesion when flowed over adherent PRBCs for 2h. The effect of rC1-2[1-179] was, however, specific for CD36-mediated adhesion and had no effect on adhesion mediated by CSA. Interference with binding of PRBCs to the vascular endothelium using rC1-2[1-179] or smaller organic mimetics may be a useful therapeutic approach to ameliorate severe complications of falciparum malaria.

Animals↗
PubMed1997

CD36 autoantibodies and thrombotic diathesis, thrombocytopenia and repeated early fetal losses.

BACKGROUND AND OBJECTIVES: Autoantibodies to CD36, a platelet glycoprotein, have been found in patients with thrombotic thrombocytopenic purpura, and in those with lupus-like anticoagulant with thrombotic complications. MATERIALS AND METHODS: Conventional hematologic and laboratory methods were used. The patient was a pregnant woman, who had had two early fetal losses separated by a normal offspring. Despite severe thrombocytopenia, she was asymptomatic. RESULTS: Serological investigations were strongly suggestive of CD36 autoantibodies. Neither clinical nor laboratory data were typical of those usually associated with cd36 autoantibodies, namely thrombotic thrombocytopenic purpura (TTP), systemic lupus erythematosis (SLE), or prothrombotic compliance. Prophylaxis with salicylates and prednisone was started at the 8th week of gestation, and an offspring with mild thrombocytopenia was delivered by cesarean section at the 32nd week of gestation because of abruptio placentae. CONCLUSIONS: There may be a cause-and-effect relationship between early fetal losses and CD36 autoantibodies.

Abortion, Habitual↗
PubMed2002

Genetics of Cd36 and the hypertension metabolic syndrome.

Although genetic mapping of quantitative trait loci (QTL) for complex traits related to hypertension is relatively straightforward, the identification of QTL at the molecular level has proven far more difficult. By combining techniques of gene mapping and gene expression profiling with studies in congenic and transgenic strains, a specific molecular defect in the Cd36 fatty acid transporter has been identified that contributes to the pathogenesis of 2 complex traits in the spontaneously hypertensive rat (SHR), namely, insulin resistance and disordered fatty acid metabolism. After mapping QTL linked to insulin resistance and dyslipidemia to the telomeric region of SHR chromosome 4, gene expression studies were used to identify candidate genes within the target chromosome segment that were differentially expressed in white adipose tissue between SHR congenic strains. This led to the identification of a major mutation in the SHR gene encoding Cd36, a fatty acid transporter involved in the transmembrane transport of long-chain fatty acids. The role for mutant Cd36 in the pathogenesis of insulin resistance and dyslipidemia was confirmed by rescuing the abnormal metabolic phenotypes through transgenic expression of wild-type Cd36 on the SHR background. These findings show that a primary defect in fatty acid transport can promote disordered carbohydrate metabolism in the SHR and show the power of advanced genome technologies for identifying QTL at the molecular level.

Animals↗
PubMed2002

A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid.

beta-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar beta-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, beta-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to beta-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by beta-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance.

Alleles↗
PubMed2002

Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages.

Modification of low density lipoprotein (LDL) can result in the avid uptake of these lipoproteins via a family of macrophage transmembrane proteins referred to as scavenger receptors (SRs). The genetic inactivation of either of two SR family members, SR-A or CD36, has been shown previously to reduce oxidized LDL uptake in vitro and atherosclerotic lesions in mice. Several other SRs are reported to bind modified LDL, but their contribution to macrophage lipid accumulation is uncertain. We generated mice lacking both SR-A and CD36 to determine their combined impact on macrophage lipid uptake and to assess the contribution of other SRs to this process. We show that SR-A and CD36 account for 75-90% of degradation of LDL modified by acetylation or oxidation. Cholesteryl ester derived from modified lipoproteins fails to accumulate in macrophages taken from the double null mice, as assessed by histochemistry and gas chromatography-mass spectrometry. These results demonstrate that SR-A and CD36 are responsible for the preponderance of modified LDL uptake in macrophages and that other scavenger receptors do not compensate for their absence.

Animals↗
PubMed2005

Myristic acid stimulates endothelial nitric-oxide synthase in a CD36- and an AMP kinase-dependent manner.

Dietary free fatty acids have been reported to have various effects on the endothelium including the generation of nitric oxide. The goal of the current study was to determine the mechanism whereby free fatty acid causes an increase in nitric oxide synthesis. The specific hypothesis tested was that free fatty acid association with CD36, a class B scavenger receptor, induces the activation of endothelial nitric-oxide synthase (eNOS). A human microvascular endothelial cell line and a transfected Chinese hamster ovary cell system were used to determine which free fatty acids stimulate eNOS. Surprisingly, only myristic acid, and to a lesser extent palmitic acid, stimulated eNOS. The stimulation of eNOS was dose- and time-dependent. Competition experiments with other free fatty acids and with a CD36-blocking antibody demonstrated that the effects of myristic acid on eNOS required association with CD36. Further mechanistic studies demonstrated that the effects of myristic acid on eNOS function were not dependent on PI 3-kinase, Akt kinase, or calcium. Pharmacological studies and dominant negative constructs were used to demonstrate that myristic acid/CD36 stimulation of eNOS activity was dependent on the activation of AMP kinase. These data demonstrate an unexpected link among myristic acid, CD36, AMP kinase, and eNOS activity.

Adenylate Kinase↗
PubMed2006

Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells.

The phagocytosis of apoptotic cells within an organism is a critical terminal physiological process in programmed cell death. Evidence suggests that apoptotic cell engulfment and removal by macrophages is facilitated by phosphatidylserine (PS) displayed at the exofacial surface of the plasma membrane; however, neither the macrophage receptors responsible for PS recognition, nor characterization of the PS molecular species potentially involved, have been clearly defined. We show that the class B scavenger receptor CD36 plays an essential role in macrophage clearance of apoptotic cells in vivo. Further, macrophage recognition of apoptotic cells via CD36 is shown to occur via interactions with membrane-associated oxidized PS (oxPS) and, to a lesser extent, oxidized phosphatidylcholine, but not nonoxidized PS molecular species. Mass spectrometry analyses of oxPS species identify structures of candidate ligands for CD36 in apoptotic membranes that may facilitate macrophage recognition. Collectively, these results identify oxPS-CD36 interactions on macrophages as potential participants in a broad range of physiologic processes where macrophage-mediated engulfment of apoptotic cells is involved.

Animals↗
PubMed2004

A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians.

CD36 is a class B scavenger receptor recognizing a variety of ligands including long-chain fatty acids and modified LDL. We investigated whether genetic variability at this locus is a determinant of free fatty acid (FFA) plasma levels and risk of coronary artery disease (CAD) in Caucasians. Typing of 21 polymorphic markers, evenly spanning the CD36 gene, revealed two linkage disequilibrium (LD) blocks that could be tagged by five polymorphisms (-33137A>G, -31118G>A, 25444G>A, 27645del>ins and 30294G>C). In 585 non-diabetic individuals of Caucasian origin, the 30294G>C polymorphism was significantly associated with FFA levels (P = 0.02)--an effect that was especially visible among men (P = 0.009). A similar association was observed in this gender at -33137 (P = 0.008) and -31118 (P = 0.028). When the five tag polymorphisms were considered together, men carrying the AGGIG haplotype had 31% higher FFA (P = 0.0002) and 20% higher triglycerides (P = 0.025) than non-carriers. The same haplotype was associated with increased risk of CAD in 197 type 2 diabetic individuals from the US (OR = 2.3, 95% CI 1.2-4.2). A similar tendency was observed in a group of 321 type 2 diabetic individuals from Italy (OR = 1.4, 0.9-2.3), resulting in an overall relative risk of 1.6 (1.1-2.3, P = 0.015) in the two populations considered together. By targeted resequencing, we identified a common variant in the CD36 promoter that is in strong LD with the AGGIG haplotype and could be partly responsible for these findings. In conclusion, this comprehensive study of CD36 variability indicates that the common polymorphisms at this locus modulate lipid metabolism and cardiovascular risk in Caucasians.

Base Sequence↗
PubMed2005

EP 80317, a ligand of the CD36 scavenger receptor, protects apolipoprotein E-deficient mice from developing atherosclerotic lesions.

CD36, a type B scavenger receptor expressed on macrophages, appears to play a major role in fatty streak formation through scavenging oxidatively modified lipoproteins in the arterial wall. We tested the hypothesis that EP 80317, a novel CD36 ligand derived from the growth hormone (GH)-releasing peptide family but devoided of any GH releasing activity, exerts anti-atherosclerotic effects in apolipoprotein E-deficient (apoE-/-) mice fed an atherogenic diet from 6 wk of age. Daily subcutaneous injections of EP 80317 (300 microg/kg) or vehicle were initiated at 6, 10, 12, or 14 wk until death at 18 wk. En face analyses of the entire aortic tree revealed a striking reduction (up to 51%) of lesion areas in EP 80317-treated apoE-/- mice compared with controls. Chronic treatment with EP 80317 (12 wk) is also associated with a 30% decrease in total plasma cholesterol, suggesting potential effects of this drug on cholesterol metabolism at the intestine/hepatic levels. EP 80317 exerts both preventive and curative effects on atherosclerotic lesion progression that were shown to be reversible after cessation of treatment. At the macrophage level, EP 80317 reduced oxidized low density lipoproteins internalization and up-regulated genes involved in cholesterol efflux, including peroxisome proliferator-activated receptor gamma (PPARgamma), liver x receptor alpha (LXRalpha), and the ATP binding cassette (ABC) transporters ABCA1 and ABCG1, supporting a role in regulating peripheral cholesterol trafficking. Importantly, the effects of EP 80317 were shown to be CD36 dependent, inasmuch as no anti-atherosclerotic or hypocholesterolemic effects were observed in apoE/CD36 double-deficient mice. In addition, long-term treatment of apoE/CD36 double-deficient mice with EP 80317 did not modulate the expression of genes of the PPARgamma-LXRalpha-ABC transporters pathway. Our results suggest that EP 80317, as a CD36 ligand, might be a prototype for a novel class of anti-atherosclerotic agents.

ATP Binding Cassette Transporter 1↗
PubMed2000

CD36 and atherosclerosis.

CD36 has been associated with diverse normal and pathologic processes. These include scavenger receptor functions (uptake of apoptotic cells and modified lipid), lipid metabolism and fatty acid transport, adhesion, angiogenesis, modulation of inflammation, transforming growth factor-beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was identified more than 25 years ago, it is only with the advent of recent genetic technology that in-vivo evidence has emerged for its physiologic and pathologic relevance. As these in-vivo studies are expanded, we will gain further insight into the mechanism(s) by which CD36 transmits a cellular signal, and this will allow the design of specific therapeutics that impact on a particular function of CD36.

Animals↗
PubMed1994

Anti-CD36 antibodies in patients with lupus anticoagulant and thrombotic complications.

Six patients with lupus anticoagulant with thrombotic complications, but not exhibiting systemic lupus erythematosus, demonstrated the presence in their plasma of antibodies directed against platelet antigens which were not detectable in two patients presenting with lupus anticoagulant but without thrombotic complications. Protein blotting of separated normal platelet proteins against patient plasma gave up to 18 bands of varying intensity indicative of multiple antiplatelet antibodies; one of these antibodies recognized a component with a mobility identical with CD36 (GPIV; m.w. 88,000) in 4/6 cases. Antibodies to CD36 and one or two other components were identified in 5/6 cases by immunoprecipitation from 125I-labelled control platelets and 6/6 by dot blots against purified CD36. These results suggest that antiplatelet antibodies and, specifically, anti CD36 antibodies, occur frequently in the plasma of patients presenting with lupus anticoagulant and thrombotic complications.

Adult↗
PubMed2006

CD36 expression and its relationship with obesity in blood cells from people with and without Prader-Willi syndrome.

Although Prader-Willi syndrome (PWS) has been linked to the loss of function of imprinted genes in 15q11q13, very little is known about the pathogenesis. Using quantitative real-time PCR, we have confirmed the previous observation of an abnormality of CD36 expression in cells with maternal uniparental disomy 15, obtained from a proband with mosaicism for PWS, by demonstrating reduced expression levels in blood cells from a series of non-mosaic probands with PWS. Furthermore, we have extended these observations to show that CD36 expression in a non-PWS population is inversely correlated with body mass index but that this correlation does not hold in PWS. CD36 which maps to 7q11.2 is the first gene outside the 15q11q13 region whose level of expression appears to be reduced in people with PWS. Low CD36 expression levels in PWS point to an abnormal control of lipid and glucose homeostasis which may explain the insatiable hunger in these patients.

Adult↗
PubMed2005

Life-threatening adverse reaction followed by thrombocytopenia after passive transfusion of fresh frozen plasma containing anti-CD36 (Nak) isoantibody.

BACKGROUND: Anti-CD36 isoantibody in blood recipients is reported to cause refractoriness to platelet (PLT) transfusions and posttransfusion purpura-like syndrome. There are few reports, however, about the effects of passively transfused blood products containing this isoantibody on recipients. CASE REPORT: A 67-year-old Japanese woman underwent brain surgery. On the 6th postoperative day, the patient experienced tightness of the chest and nausea after receiving a transfusion of fresh frozen plasma (FFP). When she manifested hypotension, the transfusion was discontinued. No cutaneous manifestation was observed. The patient's condition gradually improved soon after the administration of steroids. RESULTS: Her pretransfusion PLT count was 17.1 x 10(4) per microL. It decreased to 1.9 x 10(4) per microL 12 hours after transfusion and recovered to 15.4 x 10(4) per microL 8 days after transfusion. The donor of the FFP had a Type I CD36 deficiency. Flow cytometric analysis identified anti-CD36 isoantibody in the FFP. The cross-match between the patient's PLTs and the FFP was positive. The FFP induced the aggregation of PLTs derived from healthy adults. CONCLUSION: This is the first reported case of life-threatening adverse effects and thrombocytopenia caused by passively transfused anti-CD36 isoantibody. The possibility of passive infusion of this antibody should be considered in the evaluation of life-threatening transfusion reactions followed by thrombocytopenia.

Acute Disease↗
PubMed1993

Analysis of CD36 binding domains: ligand specificity controlled by dephosphorylation of an ectodomain.

The protein CD36 is a membrane receptor for thrombospondin (TSP), malaria-infected erythrocytes, and collagen. Three functional sequences were identified within a single disulfide loop of CD36: one that mediates TSP binding (amino acids 87 to 99) and two that support malarial cytoadhesion (amino acids 8 to 21 and 97 to 110). One of these peptides (p87-99) is a consensus protein kinase C (PKC) phosphorylation site. Dephosphorylation of constitutively phosphorylated CD36 in resting platelets and a megakaryocytic cell line led to the loss of collagen adhesion and platelet reactivity to collagen, with a reciprocal increase in TSP binding. PKC-mediated phosphorylation of this ectodomain resulted in a loss of TSP binding and the reciprocal acquisition of collagen binding. In site-directed mutagenesis studies, when the threonine phosphorylation site was changed to alanine, CD36 was expressed in a dephosphorylated state and bound to TSP constitutively.

Amino Acid Sequence↗
PubMed1993

Antigenic and functional differences in adhesion of Plasmodium falciparum-infected erythrocytes to human and bovine CD36.

Cytoadherence by Plasmodium falciparum-infected erythrocytes (PRBC) to microvascular endothelium is, in part, mediated by the specific interaction between a parasite-derived erythrocyte surface ligand and a specific binding site on human CD36. We describe the selection for increased adhesion of PRBC to bovine CD36 and demonstrate that the molecular interaction between PRBC and bovine CD36 is independent of and distinct from the OKM5/8 monoclonal antibody epitopes which block PRBC-human CD36 binding.

Animals↗