Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholesterol accumulates within smooth muscle cells and macrophages in atherosclerotic lesions, thereby contributing to the progressive enlargement of these lesions. The mechanism of this cellular accumulation of cholesterol is not known. The possibility that platelets may have a role in the cellular cholesterol accumulation that occurs during atherogenesis was investigated. Incubation of thrombin-activated washed rat platelets (or platelet-free supernatants prepared from thrombin-activated platelets) with cultured rat aortic smooth muscle cells induced cholesteryl ester lipid droplet accumulation within the smooth muscle cells. No cholesteryl ester lipid droplets accumulated when smooth muscle cells were incubated with unactivated platelets. Smooth muscle cell lipid droplet accumulation occurred in the absence of serum lipoproteins and was not inhibited by mevinolin, a drug that blocks cholesterol synthesis. These findings suggest that activated platelets may release cholesterol, which can be accumulated by cells and stored as lipid droplets.
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PMID:Platelet-mediated cholesterol accumulation in cultured aortic smooth muscle cells. 397 12

The death of a cell results in a large amount of membrane lipid, predominantly phospholipids and cholesterol, that must be eliminated. In this study, we have examined what happens to phospholipids in dying rat platelets. Rat platelets were incubated for up to three days following their activation with thrombin. Platelet death occurred during the first day of incubation. This was indicated by a complete loss of platelet lactate dehydrogenase into the incubation medium. The platelets progressively lost over one-half of their phospholipid content during the three days of incubation. Cholesterol and sphingomyelin (the phospholipid with the highest affinity for cholesterol) were not lost during the same period. Our findings suggest that significant degradation of cellular non-sphingomyelin phospholipid can be triggered by cell death. The preservation of sphingomyelin in dying platelets, may be an adaptive response to maintain cholesterol in a solubilized state within dying cells.
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PMID:Phospholipid loss in dying platelets. 828 20

An increase in levels of plasma plasminogen activator inhibitor type 1 (PAI-1) is one of the main hemostatic alterations in patients with coronary heart disease. Despite growing interest in the fibrinolytic system, few studies have been undertaken to determine the effect exerted on it by the different dietary fatty acids. We investigated the effect of a monounsaturated fat (MUFA)-rich diet in comparison with a low-fat diet (National Cholesterol Education Program step 1 diet) (NCEP-1) on factors involved in blood coagulation and fibrinolysis. We also determined the effect of dietary cholesterol on these blood parameters. Twenty-one young, male, healthy volunteers followed two low-fat/high-carbohydrate diets (< 30% fat, < 10% saturated fat, 14% MUFA) for 24 days each, with 115 or 280 mg of cholesterol per 1000 kcal per day, and two oleic acid-enriched diets (38% fat, 24% MUFA) with the same dietary cholesterol as the low-fat/high-carbohydrate diets. Plasma levels of fibrinogen, thrombin-antithrombin complexes, prothrombin fragments 1+2, plasminogen, alpha 2 antiplasmin, and tissue plasminogen activator were not significantly different among the experimental diets used in this study. Consumption of the diet rich in MUFA resulted in a significant decrease in both PAI-1 plasma activity (P < .005) and antigenic PAI-1 (P < .04) compared with the carbohydrate-rich diet (NCEP-1). The addition of dietary cholesterol to each of these diets did not result in any significant additional effect. Changes in insulin levels and PAI-1 activity were positively correlated (r = .425; P < .02). In conclusion, consumption of diets rich in MUFAs decreases PAI-1 plasma activity, which is accompanied by a parallel decrease in plasma insulin levels.
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PMID:Monounsaturated fatty acid-enriched diet decreases plasma plasminogen activator inhibitor type 1. 854 31

The cholesterol oxidation products (oxysterols) cholest-3,5-diene-7-one, cholestan-5 alpha, 6 alpha-epoxy-3 beta-ol (cholesterol 5 alpha-epoxide), cholestan-5 beta, 6 beta-epoxy-3 beta-ol (cholesterol 5 beta-epoxide), cholest-5-ene-3 beta-ol-7-one (7-ketocholesterol), cholest-5-ene-3 beta, 7 alpha-diol (7 alpha-hydroxycholesterol), cholestan-3 beta, 5 alpha, 6 beta-triol (cholestane triol), and cholest-5-ene-3 beta, 26-diol (27-hydroxycholesterol) potentiated platelet aggregation and increased thromboxane A2 formation in platelets challenged with thrombin, ADP or collagen. These effects were observed at oxysterol concentrations in the range 5-100 microM. Cholesterol 5 beta-epoxide and 7-ketocholesterol increased the mobilization of 3H-arachidonic acid from prelabelled platelet phospholipids in response to thrombin and collagen.
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PMID:The effect of cholesterol oxidation products on human platelet aggregation. 888 39

Mechanisms contributing to altered heterotrimeric G-protein expression and subsequent signaling events during cholesterol accretion have been unexplored. The influence of cholesterol enrichment on G-protein expression was examined in cultured smooth muscle cells that resemble human atherosclerotic cells by exposure to cationized LDL (cLDL). cLDL, which increases cellular free and esterified cholesterol 2-fold and 10-fold, respectively, reduced the cell membrane content of Galphai-1, Galphai-2, Galphai-3, Gq/11, and Galphas. The following evidence supports the premise that the mechanism by which this occurs is due to reduced isoprenylation of the Ggamma-subunit. First, the inhibitory effect of cholesterol enrichment on the membrane content of Galphai subunits was found to be post-transcriptional, since the mRNA steady-state levels of Galphai(1-3) were unchanged following cholesterol enrichment. Second, the membrane expression of alpha and beta subunits was mimicked by cholesterol and 17-ketocholesterol, both of which inhibit HMG-CoA reductase. Third, inhibition of Galphai and Gbeta expression in cholesterol-enriched cells was overcome by mevalonate, the immediate product of HMG-CoA reductase. Fourth, pulse-chase experiments revealed that cholesterol enrichment did not reduce the degradation rate of membrane-associated Galphai subunits. Fifth, cholesterol enrichment also reduced membrane expression of Ggamma-5, Ggamma-7upper; these gamma subunits are responsible for trafficking of the heterotrimeric G-protein complex to the cell membrane as a result of HMG-CoA reductase-dependent post-translational lipid modification (geranylgeranylation) and subsequent membrane association. Cholesterol enrichment did not alter expression of G-gamma-5 mRNA, as assessed by reverse transcriptase polymerase chain reaction, supporting a post-transcriptional defect in Ggamma subunit expression. Fifth, cholesterol enrichment also reduced the membrane content of p21ras (a low molecular weight G-protein requiring farnesylation for membrane targeting) but did not alter the membrane content of the two proteins that do not require isoprenylation for membrane association&sbd;PDGF-receptor or p60-src. Reduced G-protein content in cholesterol-laden cells was reflected by reduced G-protein-mediated signaling events, including ATP-induced GTPase activity, thrombin-induced inhibition of cyclic AMP accumulation, and MAP kinase activity. Collectively, these results demonstrate that cholesterol enrichment reduces G-protein expression and signaling by inhibiting isoprenylation and subsequent membrane targeting. These results provide a molecular basis for altered G-protein-mediated cell signaling processes in cholesterol-enriched cells.
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PMID:G-protein-mediated signaling in cholesterol-enriched arterial smooth muscle cells. 1. Reduced membrane-associated G-protein content due to diminished isoprenylation of G-gamma subunits and p21ras. 923 98

The initial step in atherosclerosis is the rapid targeting of monocytes to the sites of inflammation and endothelial injury. Serum levels of intercellular adhesion molecule-1 were found to be increased in ischaemic heart disease patients and polymorphisms in the E-selectin gene were associated with accelerated atherosclerosis in young (age < 40 years) patients, further suggesting a role of inflammation in atherosclerosis. Cholesterol loading in macrophages was found to induce interleukin-8 expression, suggesting an association between foam cell formation and beta 2-integrin-dependent adhesion of leukocytes. Enhanced endothelium-platelet interaction induced by hypercholesterolaemia is mediated by von Willebrand factor, whereas platelet adhesion to subendothelial matrix is mediated by fibulin-fibrinogen complexes. Activated platelets mediate the homing of leukocytes by interaction with the subendothelial matrix under shear stresses that do not allow neutrophil adhesion. They may also contribute to the oxidative modification of LDL, provide a source of lipids for foam cell generation and contribute to smooth muscle cell proliferation. Oxidized LDL induces tissue factor in macrophages that also provide sites for fibrin polymerization and decreases the anticoagulant activity of endothelium by interfering with thrombomodulin expression and inactivating tissue factor pathway inhibitor. Intravascular fibrinolysis induced by tissue-type plasminogen activator or urokinase may contribute to the initiation of atherosclerosis by inducing P-selectin and platelet activating factor as well as to plaque rupture, either directly or indirectly, by activating metalloproteinases. Plasminogen activator inhibitor-1 inhibits smooth muscle cell migration and, in the presence of vitronectin, promotes the clearance of thrombin by LDL receptor-related protein at sites of endothelial injury.
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PMID:Thrombosis and atherosclerosis. 933 57

Normal pregnancy is a physiological condition of balanced hypercoagulability. However, in preeclamptic pregnancies, the coagulation and fibrinolytic cascades are highly activated, accompanied by pathological blood rheology and endothelial dysfunction. This may result in disseminated intravascular coagulation (DIC). Atherosclerosis research showed that lipids may interfere with coagulation and cause endothelial dysfunction. Therefore, we analyzed the lipoprotein distribution and platelet counts in uncomplicated preeclamptic and HELLP syndrome pregnancies. In addition, a correlation between the fetal circulation determined by Doppler velocimetry and the maternal lipid metabolism was investigated. Fasting serum was collected from 24 women in the third trimester of uncomplicated pregnancies, 9 women with severe preeclampsia, and 6 women with HELLP syndrome. Cholesterol (CH), triglycerides (TGs), and apolipoproteins were analyzed in serum and in very-low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density (HDL) lipoproteins separated by ultra-centrifugation. Compared with normal pregnancies, TGs in serum, VLDL, IDL, LDL, and HDL were significantly increased in preeclampsia; no difference in CH concentrations was observed. During HELLP syndrome, IDL-TGs were increased compared with normal pregnancies. There was no clear correlation between fetal hemodynamics and maternal lipid metabolism, but there was a significant negative correlation between maternal platelet counts and serum TG levels. Because TG-rich particles may play an important role in thrombin generation and may induce platelet aggregation, the observed changes in lipoprotein metabolism in preeclampsia and HELLP syndrome may contribute to the coagulopathy seen in these conditions.
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PMID:Altered lipid metabolism in preeclampsia and HELLP syndrome: links to enhanced platelet reactivity and fetal growth. 1062 2

Glycosphingolipid- and cholesterol-enriched membrane microdomains, called rafts, can be isolated from several mammalian cells, including platelets. These microdomains appear to play a critical role in signal transduction in several hematopoietic cells, but their function in blood platelets remains unknown. Herein, we first characterized the lipid composition, including the fatty acid composition of phospholipids, of human platelet rafts. Then their role in platelet activation process was investigated. Interestingly, thrombin stimulation led to morphological changes of rafts correlating with the production of lipid second messengers in these microdomains. Indeed, we could demonstrate for the first time that a large part of the stimulation-dependent production of phosphatidic acid and phosphoinositide 3-kinase products was concentrated in rafts. Moreover, cholesterol depletion with methyl-beta-cyclodextrin disrupted platelet rafts, dramatically decreased the agonist-dependent production of these lipid signaling molecules, and impaired platelet secretion and aggregation. Cholesterol repletion restored the physiological platelet responses. Altogether our data indicate that rafts are highly dynamic platelet membrane structures involved in critical signaling mechanisms linked to the production of lipid second messengers. The demonstration of phosphatidylinositol 3,4,5-trisphosphate production in rafts may have general implications for the understanding of the role of this key second messenger found ubiquitously in higher eucaryotic cells.
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PMID:Production of phosphatidylinositol 3,4,5-trisphosphate and phosphatidic acid in platelet rafts: evidence for a critical role of cholesterol-enriched domains in human platelet activation. 1173 11

Cholesterol lowering therapy markedly reduces the frequency of subsequent cardiovascular events and is associated with a modest degree of angiographic regression of atherosclerotic lesions. There is a strong association between lipids and fibrinogen, plasminogen activator-1, and activated factor VII levels. Low density lipoprotein may be thrombogenic whereas high density lipoprotein protects against thrombosis. Lipoprotein (a) may affect atherosclerosis and thrombosis mainly by binding to fibrin and attenuating the fibrin-enhanced plasminogen activation. Tissue factor-complex initiates coagulation by activating factor X and factor IX leading in the presence of calcium to the generation of thrombin. Lipid lowering treatment with statins stabilizes atheromatous plaque and has antithrombotic effects. Therefore there are links between lipids and the haemostatic mechanisms which affect atherosclerotic, vasomotor and thrombotic components of ischemic heart disease.
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PMID:Effects of lipids on thrombotic mechanisms in atherosclerosis. 1241 62

Factor XI binds to activated platelets where it is efficiently activated by thrombin. The factor XI receptor is the platelet membrane glycoprotein (GP) Ib-IX-V complex (Baglia, F. A., Badellino, K. O., Li, C. Q., Lopez, J. A., and Walsh, P. N. (2002) J. Biol. Chem. 277, 1662-1668), a significant fraction of which exists within lipid rafts on stimulated platelets (Shrimpton, C. N., Borthakur, G., Larrucea, S., Cruz, M. A., Dong, J. F., and Lopez, J. A. (2002) J. Exp. Med. 196, 1057-1066). Lipid rafts are membrane microdomains enriched in cholesterol and sphingolipids implicated in localizing membrane ligands and in cellular signaling. We now show that factor XI was localized to lipid rafts in activated platelets ( approximately 8% of total bound) but not in resting platelets. Optimal binding of factor XI to membrane rafts required prothrombin (and Ca2+) or high molecular weight kininogen (and Zn2+), which are required for factor XI binding to platelets. An antibody to GPIb (SZ-2) that disrupts factor XI binding to the GPIb-IX-V complex also disrupted factor XI-raft association. The isolated recombinant Apple 3 domain of factor XI, which mediates factor XI binding to platelets, also completely displaces factor XI from membrane rafts. To investigate the physiological relevance of the factor XI-raft association, the structural integrity of lipid rafts was disrupted by cholesterol depletion utilizing methyl-beta-cyclodextrin. Cholesterol depletion completely prevented FXI binding to lipid rafts, and initial rates of factor XI activation by thrombin on activated platelets were inhibited >85%. We conclude that factor XI is localized to GPIb in membrane rafts and that this association is important for promoting the activation of factor XI by thrombin on the platelet surface.
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PMID:The glycoprotein Ib-IX-V complex mediates localization of factor XI to lipid rafts on the platelet membrane. 1793 92


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