Gene/Protein Disease Symptom Drug Enzyme Compound
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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

Intracellular protein transport in endothelial cells is selectively inhibited by homocysteine, a thiol amino acid associated with both thrombosis and atherosclerosis. In a previous study, homocysteine decreased cell surface expression of the surface transmembrane glycoprotein thrombomodulin without decreasing secretion of another endothelial cell protein, plasminogen activator inhibitor-1. To define further the effects of homocysteine on protein transport, we examined the processing and secretion of the multimeric glycoprotein von Willebrand factor (vWF) in human umbilical vein endothelial cells. Incubation with 2 mmol/L homocysteine resulted in complete loss of vWF multimers and prevented asparagine-linked oligosaccharide maturation, propeptide cleavage, and secretion; these effects are consistent with impaired exit from the endoplasmic reticulum (ER). Dimerization was only partially inhibited, suggesting that homocysteine causes retention of provWF in the ER without preventing dimer formation. In pulse-chase incubations, intracellular provWF was degraded before exiting the ER in homocysteine-treated cells. Homocysteine also inhibited the processing and secretion of a carboxyl-terminal truncation mutant of human provWF expressed in rat insulinoma cells, indicating that retention in the endoplasmic reticulum can be mediated by regions of provWF apart from the carboxyl-terminal 20-Kd segment. These results suggest that retention of secretory proteins in the ER is regulated by redox mechanisms and imply that the intracellular transport of multiple endothelial cell proteins may be altered in patients with homocystinuria.
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PMID:Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. 842 60

CD36, an 88 kD transmembrane glycoprotein, is an important receptor for oxidized lipoproteins. Unlike the LDL receptor, expression of CD36 is upregulated by this pro-atherogenic particle, and binding and uptake perpetuates a cycle of lipid accumulation and receptor expression. This effect is, in part, mediated by the transcription factor, peroxisome proliferator activated receptor-gamma (PPAR gamma), and its ligands. We have found that specific inhibitors of protein kinase C (PKC) reduce basal mRNA expression of CD36 and block induction of CD36 mRNA and protein by oxidized LDL (OxLDL) and a PPAR gamma ligand. In addition, PKC inhibitors block both PPAR gamma mRNA and protein expression. These results suggest that activation of CD36 gene expression by OxLDL involves activation and translocation of PKC with subsequent PPAR gamma activation. More recently, we have generated a mouse null for CD36, and crossed it with the atherogenic Apo E null strain. Evaluation of lesion development in these animals will allow us to assess the in vivo contribution of CD36 to the pathogenesis of atherosclerosis.
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PMID:CD36 in atherosclerosis. The role of a class B macrophage scavenger receptor. 1086 32

Tissue factor (TF), a transmembrane glycoprotein, initiates the extrinsic coagulation cascade. TF is known to play a major role in mediating thrombosis and thrombotic episodes associated with the progression of atherosclerosis. Macrophages at inflammatory sites, such as atherosclerotic lesions, release numerous cytokines that are capable of modulating TF expression. This study examined the role of oncostatin M (OSM), a macrophage/ T-lymphocyte-restricted cytokine, in the expression of TF in vascular smooth muscle cells (SMCs). It is reported here that OSM stimulated a biphasic and sustained pattern of TF messenger RNA (mRNA). The effect of OSM on TF mRNA expression was regulated at the transcriptional level as determined by nuclear run-offs and transient transfection of a TF promoter-reporter gene construct. OSM-induced TF expression was regulated primarily by the transcription factor NF-kappaB. Activation of NF-kappaB by OSM did not require IkappaB-alpha degradation. Inhibition of MEK activity by U0126 prevented OSM-induced TF expression by suppressing NF-kappaB DNA binding activity as determined by gel-shift analysis. Further, inhibition of Erk-1/2 protein by antisense treatment resulted in suppression of TF mRNA expression, indicating a role for Erk-1/2 in modulating NF-kappaB DNA binding activity. These studies suggest that the induced expression of TF by OSM is primarily through the activation of NF-kappaB and that activation of NF-kappaB is regulated in part by the MEK/Erk-1/2 signal transduction pathway. This study indicates that OSM may play a key role in promoting TF expression in SMCs within atherosclerotic lesions.
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PMID:Oncostatin M promotes biphasic tissue factor expression in smooth muscle cells: evidence for Erk-1/2 activation. 1115 86

CD40 is a 48-kDa phosphorylated transmembrane glycoprotein belonging to the TNF receptor superfamily. CD40 has been demonstrated on a range of cell types, and it has an important role in adaptive immunity and inflammation. CD40 has recently been described on platelets but platelet activation by CD40 has not been described. In the present study, we use flow cytometry and immunoblotting to confirm that platelets constitutively express surface CD40. CD40 mRNA was undetectable, suggesting that the protein is synthesized early in platelet differentiation by megakaryocytes. Ligation of platelet CD40 with recombinant soluble CD40L trimer (sCD40LT) caused increased platelet CD62P expression, alpha-granule and dense granule release, and the classical morphological changes associated with platelet activation. CD40 ligation also caused beta3 integrin activation, although this was not accompanied by platelet aggregation. These actions were abrogated by the CD40L blocking antibody TRAP-1 and the CD40 blocking antibodies M2 and M3, showing that activation was mediated by CD40L binding to platelet CD40. beta3 integrin blockade with eptifibatide had no effect, indicating that outside-in signaling via alphaIIbbeta3 was not contributing to these CD40-mediated effects. CD40 ligation led to enhanced platelet-leukocyte adhesion, which is important in the recruitment of leukocytes to sites of thrombosis or inflammation. Our results support a role for CD40-mediated platelet activation in thrombosis, inflammation, and atherosclerosis.
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PMID:CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. 1275 Mar 3

Tissue factor (TF) is a transmembrane glycoprotein, currently considered as being the major regulator of the coagulation cascade and the initiator of thrombogenesis in vivo. When TF comes in contact with blood, it forms a high-affinity complex with factors VII/VIIa, activating factors IX and X and thus leading to the formation of an insoluble fibrin clot. The regulation of TF-VIIa activity plays a key role in blood-vessel wall interactions. Selective patterns of cellular expression of TF are observed in tissues. TF is constitutively localized only on the surface of cells anatomically separated from the blood, where it plays an essential role in hemostasis by limiting hemorrhage after vessel wall injury. A number of pathophysiologic stimuli are capable of inducing TF transcription and activity in endothelial cells and monocytes. An aberrant TF expression in contact with blood is implicated in thrombotic complications of atherosclerosis, including acute myocardial infarction. Recent findings have demonstrated cell-derived microparticles containing TF in the circulating blood of patients with acute coronary syndromes, capable of triggering and propagating thrombus growth. This observation suggests a new view of thrombosis that does not necessarily require the exposure of vessel wall-derived TF at the site of vascular injury to initiate and propagate thrombosis.
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PMID:[Biology and physiopathology of tissue factor and its relevance for cardiovascular diseases]. 1455 84

The transmembrane glycoprotein tissue factor (TF) is the initiator of the coagulation cascade in vivo. When TF is exposed to blood, it forms a high-affinity complex with the coagulation factors factor VII/activated factor VIIa (FVII/VIIa), activating factor IX and factor X, and ultimately leading to the formation of an insoluble fibrin clot. TF plays an essential role in hemostasis by restraining hemorrhage after vessel wall injury. An overview of biological and physiological aspects of TF, covering aspects consequential for thrombosis and hemostasis such as TF cell biology and biochemistry, blood-borne (circulating) TF, TF associated with microparticles, TF encryption-decryption, and regulation of TF activity and expression is presented. However, the emerging role of TF in the pathogenesis of diseases such as sepsis, atherosclerosis, certain cancers and diseases characterized by pathological fibrin deposition such as disseminated intravascular coagulation and thrombosis, has directed attention to the development of novel inhibitors of tissue factor for use as antithrombotic drugs. The main advantage of inhibitors of the TF*FVIIa pathway is that such inhibitors have the potential of inhibiting the coagulation cascade at its earliest stage. Thus, such therapeutics exert minimal disturbance of systemic hemostasis since they act locally at the site of vascular injury.
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PMID:Tissue factor: (patho)physiology and cellular biology. 1538 18

Atherosclerosis is a dynamic disease involving lipid metabolism, inflammation and thrombosis. A key factor in thrombosis is tissue factor, a small transmembrane glycoprotein. Tissue factor binds FactorVIIa, and this complex converts Factor X to Factor Xa, leading to thrombin generation and fibrin formation. Inhibition of this pathway is by tissue factor pathway inhibitor (TFPI). Tissue factor is found sequestered within atherosclerotic plaques, and plaque rupture allows tissue factor exposure to the circulation, leading to formation of a thrombus. Tissue factor is also associated with membrane microparticles in the circulation, most likely released from monocytes activated by an inflammatory event. We hypothesize that consumption of a typical western diet that is moderate in fat content leads to elevated levels of circulating tissue factor that may act as a marker of a prothrombotic state. Healthy volunteers, aged 18-55, consumed a moderate (40%) fat meal, with blood taken before and 3.5 and 6 h after the meal. Plasma was isolated and assayed for plasma triglycerides, tissue factor, thrombin antithrombin (TAT) complexes, TFPI and TNFalpha. The levels of circulating tissue factor increased 56% (from 78 pg/ml to 120 pg/ml) 3.5 h after the meal. Levels decreased, but had not returned to baseline 6 h postprandially. No significant differences in TAT, TFPI and TNFa levels were observed postprandially. These results demonstrate increased tissue factor levels in individuals who consumed a moderate fat diet. This suggests that the typical western diet may play a larger role in cardiovascular disease than merely altering lipid profiles.
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PMID:Postprandial elevation of tissue factor antigen in the blood of healthy adults. 1626 63

CD40 is a 48kDa phosphorylated transmembrane glycoprotein that belongs to the tumor necrosis factor receptor superfamily and may play a role in formation of atherosclerotic plaques. Here, we investigated the effect of chylomicron remnants on CD40 expression in the human premonocytic cell line, THP-1 cells. Chylomicron remnants upregulated the expression of CD40 protein and mRNA in a dose- and time-dependent manner. Further, chylomicron remnants increased the generation of reactive oxygen species as determined by an increasing level of 2',7'-dichlorofluorescein. Pretreatment with the antioxidant, N-acetylcysteine, inhibited chylomicron remnant-induced CD40 protein expression by 60%. On the other hand, chylomicron remnants transiently increased the phosphorylation of extracellular signal-regulated kinase (ERK 1/2) and p38 mitogen-activated protein kinase (MAPK). Pretreatment with the MAPK kinase inhibitor, U0126, completely inhibited chylomicron remnants-induced CD40 protein expression, whereas the p38 MAPK inhibitor, SB203580, had no effect. Pretreatment with N-acetylcysteine had no effect on chylomicron remnant-induced ERK 1/2 phosphorylation. These data suggest that CD40 expression stimulated by chylomicron remnants in THP-1 cells is dependent on ERK 1/2-mediated pathway, which is followed by redox-sensitive mechanism-dependent and independent pathway. Thus, chylomicron remnants may contribute to the formation of atherosclerotic plaques via their immunological and proinflammatory effects.
Atherosclerosis 2006 Aug
PMID:Chylomicron remnants upregulate CD40 expression via the ERK pathway and a redox-sensitive mechanism in THP-1 cells. 1635 5

Tissue factor (TF) is a transmembrane glycoprotein that binds its zymogen cofactor, Factor VIIa (FVIIa) on the cell surface. Together (TF/FVIIa) they activate Factor X (FX) and Factor IX (FIX) and start the extrinsic pathway of blood coagulation. As such, the TF/FVIIa complex plays an important role in normal physiology as well as in thrombotic diseases such as unstable angina (UA), disseminated intravascular coagulation (DIC), and deep vein thrombosis (DVT). In addition to its function as an initiator of coagulation, TF/FVIIa plays an important role in inflammation. Expression of TF on the cell surface and its appearance as a soluble molecule are characteristic features of acute and chronic inflammation in conditions such as sepsis and atherosclerosis. Here we demonstrate that BCX-3607, a small molecule potent inhibitor of TF/FVIIa, reduces thrombus weight in an animal model of DVT. BCX-3607 also decreases the level of interleukin-6 (IL-6) in a LPS-stimulated mouse model of endotoxemia. Additionally, in vitro studies indicate that BCX-3607 blocks the generation of TF/FVIIa-induced IL-8 mRNA in human keratinocytes and reduces the TF/FVIIa-mediated generation of IL-6 and IL-8 in human umbilical vein endothelial cells (HUVEC). Therefore, BCX-3607 might block the TF/FVIIa-mediated coagulation and inflammation associated with pathological conditions.
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PMID:The antithrombotic and anti-inflammatory effects of BCX-3607, a small molecule tissue factor/factor VIIa inhibitor. 1637 35


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