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)

A moderate elevation of plasma homocysteine is a risk factor for atherosclerosis and arterial and veinous thrombosis. However, the mechanisms leading to vascular disorders are poorly understood because studies that have investigated the potential atherothrombogenicity of hyperhomocysteinemia in vivo are scarce. Using a rat model, we were the first to show that dietary folic acid deficiency, a major cause of basal hyperhomocysteinemia, is associated with enhanced macrophage-derived tissue factor and platelet activities. We proposed that an homocysteine-induced oxidative stress may account for this hypercoagulable state. To determine the true thrombogenicity of moderate hyperhomocysteinemia and better understand its etiology, we have carried out an acute methionine load in control and folate-deficient animals. When rats were fed the control diet, a transient fourfold increase in plasma homocysteine levels was observed 2 h after the methionine administration. As with prolonged dietary folic acid deficiency, this methionine load potentiated the platelet aggregation in response to thrombin and ADP as well as the thrombin-induced thromboxane synthesis. It also stimulated the basal and lipopolysaccharide-induced tissue factor activity of peritoneal macrophages. These prothrombotic effects were associated with an increased lipid peroxidation characterized by an elevation of plasma conjugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances. When rats were fed a folic acid-deficient diet, the methionine load did not cause any further increase in plasma homocysteine concentration, platelet activation, macrophage tissue factor-dependent coagulation, or lipoperoxidation. Altogether, our data showed that the prethrombotic state due to both the altered remethylation and transsulfuration pathways resulted from the moderate elevation of circulating homocysteine. We conclude that moderate hyperhomocysteinemia plays a role in the development of a thrombogenic state that might be mediated by the occurrence of oxidative stress.
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PMID:Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. 936 51

Tissue factor (TF) expression is associated with life-threatening thrombosis in a variety of human diseases, including sepsis, cancer, and atherosclerosis. Recently, it was shown that inactivation of the murine TF (mTF) gene results in embryonic lethality. To date, despite extensive studies on the regulation of the TF promoter in vitro, no studies have examined the cis-acting regulatory elements that control TF gene expression in vivo. Here we report that a human TF (hTF) minigene containing the human TF promoter and human TF cDNA directed a low level (approximately 1% relative to mouse TF) of both constitutive and LPS-inducible human TF expression in transgenic mice. Importantly, the human TF minigene rescued the embryonic lethality of murine TF null embryos, suggesting that human TF substituted for murine TF during embryogenesis. Rescued mice (mTF-/-, hTF+), which expressed low levels (approximately 1%) of TF activity, developed normally with no signs of a bleeding diathesis, suggesting that low TF expression can maintain hemostasis compatible with normal survival. These studies establish a novel mouse model system that can be used to examine the regulation of the human TF gene in vivo and the impact of low TF levels on the hemostatic balance in various thrombotic diseases.
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PMID:Low levels of tissue factor are compatible with development and hemostasis in mice. 944 88

Thrombotic complications are frequently associated with atherosclerosis. Lysophosphatidylcholine (LPC), a component accumulated in oxidatively modified LDL (ox-LDL), is known to play a crucial role in the initiation and progression of atherosclerotic vascular lesions. Since a vascular anticoagulant, tissue factor pathway inhibitor (TFPI), has the function of regulating the initial reaction of tissue factor (TF)-induced coagulation, we investigated the effect of LPC on TFPI synthesis in cultured human umbilical vein endothelial cells (HUVEC). The treatment of HUVEC with LPC for 24 h decreased TFPI antigen levels in both the culture medium and the cell lysate in a dose-dependent manner. Northern blot analysis revealed that LPC caused a time-dependent decrease in the TFPI mRNA levels. The levels of TFPI antigen and mRNA were decreased to 72% and 38%, respectively, by the incubation with 50 microM LPC for 24 h. The down-regulation by LPC of TFPI mRNA expression was not observed in the presence of cycloheximide, suggesting that protein synthesis was involved in the suppression of TFPI mRNA expression. The TFPI mRNA levels in actinomycin D-treated cells were relatively stable, indicating that the down-regulation of TFPI mRNA by LPC would be partly explained by the enhanced mRNA destabilization. In contrast to the significant down-regulatory effects of LPC on TFPI expression, LPC did not induce TF mRNA expression in HUVEC. These results indicate that LPC accumulated in the atherosclerotic vascular wall would suppress endothelial TFPI synthesis, reducing the antithrombotic property of endothelial cells.
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PMID:Lysophosphatidylcholine decreases the synthesis of tissue factor pathway inhibitor in human umbilical vein endothelial cells. 945 50

Statins are most potent lipid-lowering drugs. The mechanisms of their action is specific inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) activity. HMG-CoA reductase catalyses the reduction of HMG-CoA o mevalonate and is rate-limiting step in cholesterol biosynthesis pathway. Mevalonate is considered to be not only an important intermediate of cholesterol synthesis, but also the source of isoprenoids which play important role in DNA replication and cell growth. It was shown that statins inhibit the proliferation and migration of vascular smooth muscle cell--key events in atherogenesis. HMG-CoA reductase inhibitors lower the reactivity of arterial wall to vasoconstrictor agents, decrease the concentration of lipoprotein [a]--an independent risk factor of atherosclerosis, inhibit the generation of free radicals and lipid peroxidation, decrease the number of macrophages in atherosclerotic lesion and finally, equilibrate the clotting-fibrynolysis processes of attennuating platelets function, reducing the tissue factor synthesis and decreasing the concentration of plasminogen activator inhibitors. Statins are presently considered by NCEP to be the drugs of first choice for treatment of hypercholesterolemia.
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PMID:[Anti-atherosclerotic actions of HMG-CoA reductase inhibitors]. 950 89

By extrapolation from the responses of cultured human umbilical vein endothelial cells (EC) and bovine aortic EC to short-term cytokine stimulation, EC activation is postulated as a likely component of the host response in acute allograft rejection and cardiac transplant-associated accelerated arteriosclerosis. To investigate the extent to which EC activation occurs in vivo in humans and to identify potential targets for therapeutic interventions, we compared the phenotypic characteristics of vascular EC as seen during clinicopathologically significant vs non-significant acute cardiac allograft rejection. We used monoclonal and monospecific polyclonal antibodies to coagulation molecules [tissue factor, thrombomodulin (TM), antithrombin III (AT-III), fibrinogen/fibrin, cross-linked fibrin and von Willebrand factor (vWF)], adhesion molecules (P-selectin, ICAM-1) and major histocompatibility complex (MHC) class I and II molecules. In addition we sought evidence of local cytokine production (IL-1, IL-2R, IL-4, IL-6, IL-7, IL-8, TNF-alpha, PDGF-AA, PDGF-BB), which might mediate alterations in expression of these proteins. We found that in clinically significant grades of cardiac allograft rejection requiring increased immunosuppression, in contrast to lesser grades of rejection not requiring clinical intervention, there was increased microvascular EC activation and differential expression of cytokines. EC changes associated with more extensive cardiac allograft rejection requiring treatment included: (i) disruption of the normal anticoagulant state with downregulation of TM and AT-III, upregulation of tissue factor and vWF expression, and associated extensive fibrin deposition; (ii) upregulation of MHC class I antigens, which are potential targets for host cytotoxic T lymphocytes; (iii) increased expression of the leucocyte adhesion molecules P-selectin and ICAM-1; (iv) expression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha; and (v) increased expression of PDGF-AA and BB, which are known to promote migration and proliferation of intimal cells, and hence may contribute to development of transplant-associated atherosclerosis. Collectively these findings suggest that immune events resulting in EC surface changes and/or production of key cytokines play a role in the pathogenesis of acute transplant rejection and may contribute to the long-term complication of accelerated arteriosclerosis in allograft coronary arteries.
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PMID:Endothelial activation and cytokine expression in human acute cardiac allograft rejection. 953 4

Tissue factor (TF) plays a central role in the initial activation of the extrinsic coagulation pathway and is thought to be involved in the development of atherosclerosis and thrombosis. The effect of advanced glycosylation end products (AGEs) on TF expression and its mechanism were assessed by flow cytometric analysis. Human macrophage-like U937 cells, which were shown to contain mRNA encoding the receptors of advanced glycosylation end products (RAGE), expressed TF in a dose-dependent manner on incubation with AGE-albumin. AGE-albumin-induced TF expression was completely inhibited by the anti-oxidant agents, catalase and probucol. TF expression in peripheral monocytes from normal volunteers was also increased by AGE-albumin. Finally, TF expression in monocytes from individuals with diabetes mellitus, in whom the concentration of circulating AGEs is reported to be increased, was higher than that in monocytes from normal controls. These results suggest that AGE-induced TF expression in macrophages/monocytes is mediated by oxidant stress. AGEs may promote thrombosis and the development of atherosclerosis by inducing TF expression in monocytes in patients with diabetes mellitus.
Atherosclerosis 1998 Feb
PMID:Advanced glycosylation end products induced tissue factor expression in human monocyte-like U937 cells and increased tissue factor expression in monocytes from diabetic patients. 954 99

In health, the vascular endothelium forms a multifunctional interface between the circulating blood and various tissues and organs of the body. It constitutes a selectively permeable barrier for macromolecules, as well as a nonthrombogenic and nonadhesive container that actively maintains the fluidity of blood. It is a metabolically active endocrine organ, serving as the source of multiple factors and mediators that are critical for normal homeostasis. These include vasodilators (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor), vasoconstrictors (endothelin-1, thromboxane A2, prostaglandin H2 and components of the renin angiotensin system), various pro- and antithrombotic factors (e.g. tissue factor, platelet activating factor--PAF, von Willebrand factor), fibrinolytic activators and inhibitors (e.g. tissue plasminogen activator, plasminogen activator inhibitor-1), potent arachidonate metabolites (prostanoids), leukocyte adhesion molecules (e.g. E-selectin, P-selectin, intercellular adhesion molecule-1--ICAM-1, vascular cell adhesion molecule-1--VCAM-1), and multiple cytokines with activities of growth stimulators and inhibitors, transforming growth factors, proinflammatory and antiinflammatory mediators, tumour necrosis factors and chemotactic factors (chemokines). Besides these essential activities controlling the cardiovascular system, the endothelial cells represent an important part of the immune system as well. They have a pivotal role in the initiation and development of defensive and damaging inflammatory responses. Therefore endothelium can be considered as being the central equipment for the mutual exchange of life important information between the cardiovascular and immune systems. This in turn is leading to rapid advances in understanding the pathogenesis of some of the most serious and most common diseases, including inflammation, atherosclerosis and hypertension. (Tab. 7, Ref. 89.)
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PMID:[Vascular endothelium as a factor in information transfer between the cardiovascular and immune systems]. 958 73

The "American Heart Association Committee on Vascular Lesions" suggests the following morphologic classification of atherosclerotic plaques: the classification is based on large autopsy studies facilitating the assessment of the natural course of atherosclerotic lesions at precisely defined progression prone areas of the coronary tree from their clinically silent beginning to the stage where they produce symptoms. Lesion evolution is divided in 5 phases reflecting the possible time course of plaque development. Each phase is characterized by plaques with a distinctive morphology. The classification offers a framework of typical morphologies which the results of clinical investigations may be related to. Looking at the plaque composition, it is readily conceivable that atherosclerosis shares many characteristics with the general pathology of chronic inflammation and wound healing. Clinical symptoms e.g. acute coronary syndromes, arise from inflammation-mediated endothelial erosion and/or plaque rupture with ensuring coronary thrombosis. Advanced or complicated plaques are composed of different kinds of constituents in varying proportions. However, plaques at risk display a large lipid core occupying more than 40% of the plaque's volume, increased numbers of macrophages, reduced numbers of smooth muscle cells, an increased expression of tissue factor, and a thin plaque cap. Functionally, active plaques are characterized by a locally enhanced vasoreactivity with evidence coming from our own recent investigations that localised chronic inflammatory processes within the atherosclerotic plaque are responsible not only for the plaque rupture itself, but also for the hyperreactivity of these vessels to vasoconstrictor stimuli. In this context endothelin 1 (ET-1), a very potent vasoconstrictor peptide, may play an important role. ET-1 was originally reported to be produced by endothelial cells and to act locally in a paracrine fashion to regulate vascular tone. However, further studies have clarified that ET-1 is not only produced by endothelial cells but also by human inflammatory cells suggesting a role for ET-1 in inflammatory processes. Additionally, ET-1 displays a potent mitogenic activity. We examined immunohistochemically the presence of ET-1 in coronary plaque tissue obtained by directional coronary atherectomy. ET-1 immunoreactivity preferentially localized in plaque components indicative of a chronic inflammatory process. In addition, semiquantitative analysis of ET-1-like immunoreactivity revealed significantly higher staining grades in active coronary lesions compared with nonactive lesions. The increased ET-1 content in active coronary lesions may be beneficial to the stabilization of the vessel wall after plaque rupture and disadvantageous because it may lead to vasospasm and to the progression of atherosclerosis.
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PMID:[Pathomorphology of coronary atherosclerosis]. 959 3

Plasma von Willebrand factor antigen, soluble thrombomodulin, and tissue factor were increased in 31 patients with severe chronic renal failure (creatinine clearance <20 ml/min) under conservative treatment, whereas plasminogen activator inhibitor antigen did not differ significantly from healthy controls. No correlation among plasma levels of these proteins was found. Three patterns of relationship between endothelial cell markers and hemostatic defects were identified: 1) Plasma thrombomodulin, a marker of endothelium damage, was found an independent predictor of bleeding time and platelet aggregation, and secretion defects, and was also related to the severity of renal failure; 2) von Willebrand factor antigen, an index of endothelial cell activation and secretion, was significantly correlated with intravascular markers of thrombin and plasmin generation and with platelet adenosine triphosphate content, but not with plasma creatinine levels; and 3) tissue factor and plasminogen activator inhibitor antigen levels were not statistically correlated with the diverse hemostatic defects. Activation of coagulation and fibrinolysis, secondary to endothelial cell activation, appearing early during the evolution of chronic renal failure, is pathogenically related to the platelet dysfunction, and probably to development of atherosclerosis and thrombotic events in this disease. The progression of chronic renal failure, through endothelial cell damage, would lead to aggravation of the platelet functional defect potentiating the hemorrhagic risk.
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PMID:Endothelial cell markers in chronic uremia: relationship with hemostatic defects and severity of renal failure. 961 Sep 57

Herpes simplex virus type 1 and cytomegalovirus alter the phenotype of the endothelium in vitro from anticoagulant to procoagulant, thereby promoting the adherence of neutrophils and platelets to the endothelium. Virus infection of the endothelium induces the expression of viral glycoproteins and adhesion molecules, which promote neutrophil and monocyte adhesion. Herpes simplex infection of the endothelium promotes prothrombinase assembly, allowing more efficient thrombin generation. Excess thrombin generation causes translocation of P-selectin. Viral infection also induces the procoagulant molecule, tissue factor, in endothelial cells. These enhanced procoagulant effects are associated with the loss of anticoagulants, including thrombomodulin, prostacyclin and tissue plasminogen activator. These studies support the speculation that virus infection in vivo promotes vascular injury and thrombosis, which may contribute to disease states such as atherosclerosis.
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PMID:Effects of viral activation of the vessel wall on inflammation and thrombosis. 966 64


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