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)

The expression of tissue factor (TF), the principal initiator of coagulation, is increased during inflammation and atherosclerosis. Both conditions are promoted by lysophosphatidylcholine (lysoPC). We observed in the present study that lysoPC (1 to 10 micromol/L) dose-dependently reduced TF activity in human monocytes, as elicited by lipopolysaccharide (LPS). Lysophosphatidylethanolamine (lysoPE) and other lysophospholipids did not affect LPS-induced TF activity of human monocytes. TF antigen expression as elicited by LPS was also lowered by lysoPC. Phospholipid analyses indicated a selective increase in the lysoPC content of the monocytes after preincubation with the lysophospholipid. LysoPC inhibited the TF activity of Mono Mac-6 cells to a similar extent as in the monocytes. LPS binding to plasma membrane receptors and internalization of LPS into monocytes were not affected by lysoPC. In contrast, LPS-mediated nuclear binding of nuclear factor-kappaB/Rel to a TF-specific kappaB site was inhibited by lysoPC. Induction of TF mRNA expression by LPS tended to be partially reduced by the lysophospholipid. Preincubation with lysoPC increased monocytic cAMP levels. Inhibition of adenylyl cyclase by pretreatment with 2'-deoxy-3'-adenosine monophosphate partially reversed the inhibition of TF activity promoted by lysoPC. In conclusion, lysoPC markedly decreases LPS-mediated TF expression of human monocytes, the effect probably being mediated by both transcriptional and posttranscriptional mechanisms. LysoPC may thus attenuate activation of coagulation during inflammation and atherosclerosis.
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PMID:Tissue factor expression of human monocytes is suppressed by lysophosphatidylcholine. 988 65

Aspirin is the most widely prescribed agent to reduce the platelet-mediated contributions to atherosclerosis, coronary thrombosis and restenosis after angioplasty. While aspirin treatment has led to significant reductions in morbidity and mortality in many clinical trials, there are several scenarios in which aspirin may fail to provide a full antithrombotic benefit. The cyclic flow model of experimental coronary thrombosis suggests that elevations of plasma catecholamines, high shear forces acting on the platelets in the stenosed lumen and the presence of multiple, input stimuli can activate platelets through different mechanisms that may lead to thrombosis despite aspirin therapy. Aspirin therapy is limited because it only blocks some of the input stimuli, leaving aspirin-independent pathways through which coronary thrombosis can be precipitated. These include thrombin and thrombogenic arterial wall substrates such as tissue factor. New agents that block the adenosine diphosphate (ADP) receptor, or regulate platelet free cytosolic calcium, such as direct nitric oxide donors, may be more potent overall than aspirin. Agents that block the platelet integrin GPIIb-IIIa receptor inhibit the binding of fibrinogen to platelets regardless of which input stimuli activate the platelet and, thus, as demonstrated in the cyclic flow model, would be much more potent than aspirin as an antithrombotic agent. The cyclic flow model has been useful in predicting which agents are likely to be of benefit in clinical trials.
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PMID:A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials. 997 6

Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden coronary death. Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. Therefore, we have to focus on plaque composition and vulnerability to rupture and plaque thrombogenicity rather than on plaque size and stenosis severity. The risk for plaque disruption depends more on plaque vulnerability (plaque type) than on degree of stenosis (plaque size). Lipid-rich and soft plaques are more vulnerable and prone to rupture than collagen-rich and hard plaques. They are also highly thrombogenic after disruption because of high content of tissue factor. There seems to be three major determinants of a plaque's vulnerability to rupture: 1) the size and consistency of the lipid-rich atheromatous core, 2) the thickness of the fibrous cap covering the core, and 3) ongoing inflammation and repair processes within the fibrous cap. Lipid accumulation, cap thinning, lack of smooth muscle cells (smc), and macrophage-related inflammation destabilize plaques, making them vulnerable to rupture. In contrast, smc-related healing and repair processes stabilize plaques, protecting them against disruption. Plaque size or stenosis severity tell nothing about a plaque's vulnerability. Many vulnerable plaques are invisible angiographically due to their small size and compensatory vascular remodeling.
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PMID:Plaque pathology and coronary thrombosis in the pathogenesis of acute coronary syndromes. 1038 96

The procoagulant activity of tissue factor is regulated by circulating inhibitors such as tissue factor pathway inhibitor (TFPI) and LDL. These 2 inhibitors also readily associate making the distinction between their activities difficult. We have examined the relative contributions of intact and C-terminal truncated TFPI and ApoB100. By following the inhibitory potential of the preparations, over a period of 120 minutes, it was demonstrated that TFPI and LDL-resembling particles inhibited tissue factor at different rates. TFPI was found to be a short, fast-acting inhibitor, whereas the action of LDL-resembling particles was more prolonged but slower. The oxidation of LDL has been closely associated with the development of cardiovascular disease, including atherosclerosis and thrombosis. Positively charged amino acids, particularly lysine residues, are prone to alterations via the formation of adducts by lipid peroxidation products. These residues are important in the inhibition of tissue factor activity by ApoB100. They also play an important role in the inhibitory Kunitz domains of TFPI. We have shown that the decline in the ability of LDL to inhibit tissue factor was as a result of modifications in LDL arising from oxidation. By examining the effects of oxidation on full-length and C-terminal truncated TFPI bound to LDL-resembling particles, we found that TFPI is only affected when in close association with ApoB100. C-terminal truncated TFPI was not affected significantly by oxidation. Finally, chemical modification of lysine and arginine residues reduced the overall inhibition of tissue factor by TFPI. We propose that TFPI and LDL act separately to inhibit tissue factor in vivo. However, the oxidation of LDL can alter both the endogenous activity of ApoB100 and reduce that of closely associated TFPI, compromising normal hemostasis.
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PMID:Comparison of the inhibitory effects of ApoB100 and tissue factor pathway inhibitor on tissue factor and the influence of lipoprotein oxidation. 1039 99

Thrombosis is a key feature of the initiation and progression of atherosclerosis and its clinical sequelae. Acute thrombosis can lead to arterial occlusion and consequently provoke myocardial infarction, unstable angina, stroke and sudden death. Acute thrombosis can also be a complication of arterial bypass surgery, balloon angioplasty, atherectomy, or coronary artery stenting. The thrombotic response is influenced by several factors, among them the thrombogenicity of the vessel wall and of certain blood components as well as their interaction with the lipid pool. Tissue factor (TF) is considered to be the primary cofactor of cellular origin that is involved in activation of the coagulation pathway. The active form of TF has been shown to be present in specimens of human coronary artery in association both with acellular lipid areas and with macrophages and smooth muscle cells, which suggests that TF plays a major role in determining plaque thrombogenicity. We discuss here what is currently known about the role of tissue factor in atherogenesis, and focus attention on pharmacological approaches in this area.
Atherosclerosis 1999 Jun
PMID:Tissue factor in atherosclerosis. 1040 89

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.
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PMID:[Blood coagulation and fibrinolysis in arteriosclerosis]. 1041 53

Atherosclerosis is vascular disease characterized by thickening, hardening, and remodelling of the arterial wall. Occlusive vascular disease most often results from thrombosis superimposed on atherosclerotic plaque. Lipoproteins enter the vessel wall, promoting the recruitment of monocytes, which imbibe lipids and become foam cells. Smooth muscle cells invade these early plaques, producing connective tissue fibrils that form a fibrous cap over the lipid center; rupture of this cap is an important cause of thrombosis. The specific topography of early atherosclerotic lesions is primarily attributed to wall shear stress, one of hemodynamic forces. Inflammatory mediators regulate processes that determine the composition of the plaque's fibrous cap, a structure that separates blood from the thrombogenic lipid core. Factors involved in coagulation, such as thrombin, can regulate non-thrombotic functions of vascular wall cells such as smooth muscle proliferation or cytokine release. Tissue factor is a major regulator of coagulation and hemostasis. When the plaques are ruptured or eroded, exposure of cellular and extracellular tissue factor to circulating blood play a pivotal role in mediating fibrin-rich thrombus formation leading to acute coronary syndromes. Several serial angiographic studies have demonstrated that over 70% of acute coronary syndromes evolve from mildly to moderately obstructive atherosclerotic plaques.
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PMID:[Atherosclerosis]. 1042 66

Atherosclerosis is a systemic disease of the large arteries, and activation of inflammatory pathways is important in its pathogenesis. Increasing evidence supports the importance of CD40-CD154 interactions in atherosclerosis, interactions originally known to be essential in major immune reactions and autoimmune diseases. CD40 is present on atheroma-derived cells in vitro and in human atheromata in situ. Ligation of CD40 on atheroma-associated cells in vitro activates the production of chemokines, cytokines, matrix metalloproteinases, adhesion molecules and tissue factor, substances responsible for lesion progression and plaque destabilization. Administration of antibody against CD154 to low-density lipoprotein receptor-deficient mice has been shown to reduce atherosclerosis and decrease T-lymphocyte and macrophage content; however, only initial lesions were studied. Here, we determined the effect of genetic disruption of CD154 in ApoE-/- mice in both initial and advanced atherosclerotic lesions. Plaque area was reduced 550%. In contrast to previous reports, initial lesion development was not affected. Advanced plaques in CD154-/-ApoE-/- mice had a less-lipid-containing, collagen-rich, stable plaque phenotype, with a reduced T-lymphocyte/macrophage content. These data indicate that CD40-CD154 signaling is important in late atherosclerotic changes, such as lipid core formation and plaque destabilization.
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PMID:Requirement for CD154 in the progression of atherosclerosis. 1054

Inflammation and activation of immune cells have important roles in the pathogenesis of atherosclerosis. We analyzed the plasma levels of inflammatory markers and the degree of activation of peripheral blood monocytes and T-lymphocytes isolated from 12 unstable angina, 12 stable angina, and 12 normal subjects. In 20%-33% of patients, monocytes expressed high basal levels of IL-8, tissue factor, IL-1beta, and monocyte chemoattractant protein-1 mRNA. Furthermore, basal mRNA levels of these cytokines showed strong correlation with each other (p < 0.01 in all combination) but not with tumor necrosis factor-alpha or transforming growth factor-beta1. Plasma level of C-reactive protein was highest in the unstable angina patients (1.63+/-0.70 mg/l) and lowest in the control subjects (0.22+/-0.08 mg/l) (P = 0.03). We also observed a high correlation between C-reactive protein level and the occurrence of minor and major coronary events during 6 months of follow-up. Activation status of T-cells, assessed by the percentage of HLA-DR positive cells, was highest in the unstable angina patients (26.8+/-1.4%) compared with that in the control (14.7+/-1.2%) (P = 0.0053). Our data represent the first case showing that the circulating monocytes in angina patients are activated to a state express numerous proatherogenic cytokines. These results may help to diagnose angina patients according to the inflammatory markers and evaluate the prognosis of the disease.
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PMID:Activation of monocytes, T-lymphocytes and plasma inflammatory markers in angina patients. 1055 Dec 65

Hyperhomocysteinaemia has been associated with arterial and venous thrombosis possibly by causing damage to the endothelium. We hypothesised that an oral load in methionine, that increases plasma homocysteine, would also result in an increase in biological markers of endothelial or platelet dysfunction. Then we investigated two groups of patients with arterial or venous occlusive disease: 17 with hyperhomocysteinemia and 12 without hyperhomocysteinemia. We measured in both groups plasma soluble thrombomodulin, von Willebrand factor, P-selectin and tissue factor plasma inhibitor before and 6 hours after a load with 100 mg/kg oral methionine. Methionine load resulted in a significant increase in von Willebrand factor in both groups (P<0.02), suggesting that endothelial dysfunction occurs during the load.
Atherosclerosis 1999 Dec
PMID:Endothelial dysfunction during acute methionine load in hyperhomocysteinaemic patients. 1055 28


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