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

Platelet adhesion to VLDL, LDL, HDL, and to a mixture of purified apolipoproteins was examined. Platelets adhered to all the classes of lipoproteins tested. VLDL and the apolipoprotein mixture promoted the greatest degree of adhesion. Platelet adhesion was inhibited by addition of EDTA, RGD-containing peptides and anti-GPIIb-IIIa, monoclonal antibodies. Platelets from patients with Glanzmann's Thrombasthenia which lack the GPIIb-IIIa receptor adhered to VLDL less than half as well as did normal platelets. These results demonstrate that the major circulating lipoproteins can mediate in vitro platelet adhesion and that this adhesion occurs via platelet integrin receptors. We postulate that lipoprotein mediated platelet adhesion may play an important role in the progression of atherosclerosis.
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PMID:Plasma lipoproteins mediate platelet adhesion. 222 60

A role of von Willebrand factor-mediated platelet function in porcine atherogenesis is strongly suggested by these studies. This influence of platelet function is probably most important in experimental systems that involve long-term observation and low or moderately elevated levels of serum cholesterol. On the other hand, effects of platelet function on development of atherosclerosis in animals with extremely high serum cholesterol levels are difficult to demonstrate and may be of relatively less importance. These observations are consistent with the results of numbers of recent studies describing the relationship of vascular injury to intimal smooth muscle cell proliferation. There is considerable evidence that lipid-rich intimal lesions occur in hypercholesterolemic animals with no antecedent denudation of endothelium or platelet adherence. It is difficult to ascribe intimal proliferation to platelet effects in this setting. On the other hand, endothelial cells, smooth muscle cells, and monocytes, which are all known to be involved in the atherosclerotic process, can produce mitogenic and chemotactic proteins, including platelet-derived growth factor. Therefore, metabolic aberrations of various kinds, including those initiated by mechanical injury or hypercholesterolemia, may promote proliferation in the vascular wall and resultant lesion development. Data from studies of pigs with vWD suggest a contribution of platelets to this process, but the effects of this contribution are modulated by numbers of variables, most of which are yet to be identified. The control of these multiple variables will be necessary before a clear understanding of the magnitude of the platelet-mediated effects can be gained. This will require carefully defined conditions of hypercholesterolemia, special attention to the immunologic variables and study of properly selected vascular segments under known conditions of flow. This later element will be especially important in the study of vWF-mediated platelet function, since shear forces are a critical determinant of vWF function. Systems that model flow conditions in various segments of the aorta, carotid, and coronary arteries are presently under development for this purpose. Finally, studies examining the molecular basis of vWF-mediated and other platelet functions will probably guide the most productive use of these models. Platelet membrane glycoprotein (GP) receptor Ib and the complex GP IIb and IIIa have been shown in ex vivo studies to be binding sites for vWF molecules.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Porcine von Willebrand disease: implications for the pathophysiology of atherosclerosis and thrombosis. 355 Aug 94

This review concerns our understanding of the molecular basis of platelet function in haemostasis. In particular, we indicate how research into platelet membrane glycoprotein (GP) receptors is yielding vital information on the mechanisms of platelet adhesion and aggregation. These receptors, nearly always complexes of two or more subunits, are now known to belong to distinct gene families, some of which are unique to platelets while others are widely distributed in mammalian tissues. GP Ib-IX complexes are responsible for the high-shear-rate-dependent adhesion of platelets to von Willebrand factor (vWF) exposed within the subendothelium of damaged vessels. Other adhesion receptors include members of the VLA subclass of the integrin family: VLA-2, VLA-5 and VLA-6, which mediate platelet adhesion to collagen, fibronectin and laminin, respectively. Platelet aggregation is initiated by distinct populations of receptors specific for each physiological agonist. Many of these receptors, including the highly important and recently cloned thrombin receptor, have seven transmembrane domains and possess highly selective agonist-binding determinants. Finally, we highlight platelet aggregation and the role of GP IIb-IIIa complexes which, following platelet activation, bind fibrinogen and other adhesive proteins. The latter, through being polyvalent for GP IIb-IIIa, then form the bridges linking adjoining platelets. The 'ligand-binding pocket' of GP IIb-IIIa contains at least three sequences essential for ligand binding; fibrinogen also binds to the activated complex through identified domains, one of which, the Arg-Gly-Asp (RGD) sequence, is also found in vWF and the other adhesive proteins able to support platelet aggregation. Finally, we further describe how these, and other glycoproteins in both surface and internal membrane systems, constitute a complex receptor network capable of translocation and reorganization after platelet activation. In cardiovascular disease, platelets accumulate within arteries whose luminal surface has been modified through atherosclerosis. Recent molecular advances are yielding exciting opportunities for the development of new, and more powerful, drugs acting as specific inhibitors of thrombotic processes.
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PMID:A review of the role of platelet membrane glycoproteins in the platelet-vessel wall interaction. 802 47

The deposition of platelets at the site of balloon angioplasty is thought to play a major role in the pathogenesis of restenosis. The antibody AZ-1, which binds to the rabbit platelet glycoprotein IIb/IIIa receptor and inhibits platelet function both in vitro and in vivo, was produced and tested in an experimental model of angioplasty. Atherosclerosis was induced by desiccation injury of the femoral artery, followed by a 28-day diet with 2% cholesterol and 6% peanut oil. Rabbits were randomized to receive an infusion of saline, a single infusion of 0.5 mg/kg of AZ-1, or an infusion of 0.6 mg/kg AZ-1 before angioplasty. The latter group received a second infusion of 0.6 mg/kg 72 hours later. Functional platelet inhibition was demonstrated by prolongation of the bleeding time in all treated animals. Angiography was performed at baseline, immediately after a standardized angioplasty, and again 28 days after angioplasty on a total of 42 vessels. There were no significant differences between the antibody-treated group and the control group in the mean angiographic minimum luminal diameter at any of the time points. There was also no difference in the initial improvement after angioplasty (acute gain), in the decrease in luminal diameter from immediately after angioplasty to 28 days after angioplasty (late loss), or in the overall improvement from before angioplasty to 28 days after angioplasty. Quantitative histological analysis confirmed the lack of a beneficial effect of AZ-1. There were no significant differences in the area of the intima, the media, or the combined intima and media between the antibody-treated groups and the control group. Thus, potent platelet inhibition for up to 6 days after balloon angioplasty using a monoclonal antibody that inhibits platelet aggregation did not reduce the response to vascular injury after balloon angioplasty in this rabbit model of experimental atherosclerosis.
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PMID:Preparation, characterization, and evaluation of a monoclonal antibody against the rabbit platelet glycoprotein IIb/IIIa in an experimental angioplasty model. 803 40

Lipoprotein(a) [Lp(a)] plays an important role in atherosclerosis. The amino acid sequence of apolipoprotein(a) [apo(a)] reveals an arginyl-glycyl-aspartate (RGD) tripeptide that is the consensus sequence for binding of adhesive plasma proteins of the fibrinolytic system, such as fibrinogen and von Willebrand factor, to the platelet membrane glycoprotein IIb-IIIa (GPIIb-IIIa) complex. Therefore, we undertook the present study to further investigate the role of Lp(a) in hemostasis. Binding of 125I-Lp(a) to a single platelet membrane-associated protein (137 +/- 6 kD) comigrating with platelet GPIIb (140 kD) was found to be specific, saturable, and Ca2+ independent. Binding of 125I-Lp(a) to resting human blood platelets was saturable, insensitive to temperature, and independent of the apo(a) isoform (B, S1 through S3). Scatchard analysis revealed a Kd of 7.2 +/- 1.8 x 10(-9) mol/L, with 729 +/- 313 Lp(a) molecules bound per platelet. Monoclonal anti-GPIIb IgG diminished Lp(a) binding by approximately 80%, monoclonal anti-GPIIb-IIIa IgG by 60%, and anti-GPIIIa IgG by just 15%. 125I-Lp(a) binding was competitively inhibited to the same extent by either unlabeled Lp(a) or fibrinogen. Low- and high-density lipoproteins were much weaker competitors. A polyclonal antibody raised against the RGDGQSYRGT sequence of apo(a) was used to verify the presence of an RGD sequence in the different Lp(a) preparations investigated. However, two lines of evidence indicated that the RGD sequence is not the binding domain mediating Lp(a) binding to platelets. First, incubation of platelets with isolated RGD tripeptide did not influence Lp(a) binding.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of glycoprotein IIb as the lipoprotein(a)-binding protein on platelets. Lipoprotein(a) binding is independent of an arginyl-glycyl-aspartate tripeptide located in apolipoprotein(a). 812 37

The binding of fibrinogen to its receptor on mammalian platelets and avian thrombocytes has been extensively studied; and the receptors, composed of glycoproteins IIb and IIIa, have been characterized in both systems. Recently, monocytes have been implicated in the thrombotic complications of atherosclerosis, and in both the avian and human systems this appears to be through a procoagulant activity which leads to fibrinogen polymerization. Although fibrin polymerization by avian monocytes has been reported, the receptor for fibrinogen on these cells has not been reported previously. The present study describes the presence of glycoprotein IIb- and IIIa-like proteins in avian macrophages and correlates the localization of these glycoproteins with regions to which fibrinogen binds. Through the use of immunofluorescence light microscopy and immunogold electron microscopy in conjunction with monospecific, polyclonal antibodies, GPIIb and GPIIIa cross-reacting antigens were identified on membranes of monocyte/macrophages cultured from White Carneau pigeons. A specific concentration of the antigens was found on membrane ruffles and microvilli, sites to which FITC-labeled fibrinogen also bound. Interaction of the antibodies with pigeon macrophages was confirmed by enzyme-linked immunosorbent assays with cultured cells. Immunoblotting of membranes isolated from pigeon monocyte/macrophages identified a protein of 132,000 M(r) that was recognized by anti-GPIIb and a protein of 114,000 M(r) that was recognized by anti-GPIIIa. These pigeon monocyte glycoproteins comigrated with glycoproteins IIb and IIIa isolated from human platelets.
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PMID:Glycoprotein IIb/IIIa cross-reacting antigen in monocyte-derived macrophages from the pigeon. 822 17

Binding of fibrinogen to platelets washed from the blood of patients with hypercholesterolemia and hypertriglyceridemia (n = 25) and control donors (n = 12) was compared. In addition, the content of platelet glycoprotein IIb was determined by radioimmunoassay. Fibrinogen was bound in significantly higher amounts (P < 0.02) to hyperlipidaemic platelets activated by ADP than to control ones (107,112 +/- 16,371 and 45,612 +/- 6495 molecules per platelet, respectively). The mean content of GPIIb was the same in hyperlipidaemic and in control platelets (2.06 +/- 0.16 and 1.94 +/- 0.21 micrograms/10(8) platelets, respectively). The amount of fibrinogen bound to the activated hyperlipidaemic platelets showed a positive correlation with total plasma cholesterol and LDL (r = 0.45 and 0.47, respectively) whereas a negative correlation with plasma HDL was found (r = -0.50). The increased expression of fibrinogen binding sites similar to that of hyperlipidaemic platelets could be produced by preincubation of normal platelets with palmitic acid. This was evidenced by a significant increase of fibrinogen binding sites in control platelets. This suggests that either palmitoylation of the receptor or microenvironment changes in the membrane lipid bilayer may be responsible for the enhanced platelet receptor capacity to bind fibrinogen.
Atherosclerosis 1993 Oct
PMID:Increased platelet-fibrinogen interaction in patients with hypercholesterolemia and hypertriglyceridemia. 828 Jan 81

von Willebrand factor (vWf) is synthesized by vascular endothelial cells and megakaryocytes, and is present in plasma, platelets and subendothelium as a large multimeric glycoprotein that has a dual role in hemostasis. vWf mediates the adhesion of platelets at the site of vascular injury by linking to specific platelet membrane receptors (glycoprotein [GP] Ib-IX complex) and to constituents of subendothelial connective tissue. vWf also functions as a carrier protein for factor VIII; this interaction is necessary for normal factor VIII survival in the circulating plasma. Each vWf subunit has binding sites for collagen, heparin, GP Ib, GPIIb/IIIa and factor VIII. Deficiency of vWf results in defective platelet adhesion and a secondary deficiency of factor VIII, both causing abnormal bleeding. In addition, vWf plays an important role in thrombogenesis and the development of atherosclerosis.
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PMID:[Biosynthesis in the vascular endothelial cells, molecular structure and function of von Willebrand factor]. 832 Aug 43

The haemostatic response of platelets of any one individual will be influenced by the genetic profile of the total population of receptors expressed on the platelet surface. Among the parameters to consider will be (i) the density of each receptor, (ii) the rate at which genes are transcribed and receptors produced and (iii) the presence or not of structural polymorphisms. Already, consideration of the known polymorphisms on GP IIb and GP IIIa raises most interesting questions on the structure/function relationship for this receptor. For example, there is often no obvious pattern as to which polymorphisms will influence platelet function and which will risk giving rise to a diallelic alloantigen system. Thus, mutation at Arg214 results in a loss in the ability of the complex to support platelet aggregation, whereas a mutation at Arg143 has resulted in the production of an immune response (see above). As I have pointed out earlier, examples from inherited platelet disorders show that even a single mutated allele can influence receptor function. Others have shown that polymorphisms of plasma proteins (see 52) or membrane glycoproteins such as E-selectin of endothelial cells (see 53) can give rise to risk factors for thrombosis and/or atherosclerosis. It would be interesting to know whether polymorphisms of platelet glycoprotein receptors (and those shared with other vascular cells) also represent risk factors in cardiovascular disease.
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PMID:Polymorphisms of human platelet membrane glycoproteins: structure and clinical significance. 857 82

Platelets are activated by contact with vascular lesions in high flow arteries and are involved in the development of thrombosis, atherosclerosis and the complications of transluminal angioplasty. Hence platelets are one the targets of pharmacological intervention in the prevention and treatment of arterial thrombosis. Understanding of the mechanisms of activation of platelet has enabled the development of new antiplatelet agents and the improvement of their therapeutic usage. The most recent clinical drugs and those currently under development belong to two main families: antagonists of the membrane receptors of activation coupled to signal transducting G proteins which fix circulating stimuli such as ADP, thrombin and TXA2 and inhibitors of the binding of adhesive proteins such as fibrinogen to the GPIIb-IIIa integrin or of von Willebrand factor to the leucine-rich glycoprotein complex GPIb-V-IX.
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PMID:[Mechanisms of platelet activation and development of antiplatelet agents]. 909 10


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