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)

Thrombomodulin plays a role as a cofactor for thrombin-catalyzed activation of protein C on endothelial cells. We examined the effect of homocysteine, a stimulant of atherosclerosis and thrombotic disease, on the cofactor activity and protein level of thrombomodulin and also on the expression of thrombomodulin in endothelial cells. Homocysteine inhibited the cofactor activity of thrombomodulin both on the surface of endothelial cells and in the whole cells dose- and time-dependently, and maximal inhibition of the cofactor activity occurred after a 3- to 6-hour incubation with 10 mmol/L homocysteine (10% of initial activity). Homocysteine also decreased the amount of intact (unreduced) thrombomodulin in endothelial cells. However, at the same condition the total protein level (reduced and unreduced form) of thrombomodulin, determined by dot immunoblot analysis using the monoclonal antibody that recognized both reduced and unreduced thrombomodulin, decreased slightly, and the mRNA level of thrombomodulin showed a twofold to three-fold increase. After 24 hours of incubation, the cofactor activity and total protein level of thrombomodulin were 60% and 165% of the initial values, respectively. When purified thrombomodulin fixed to a microwell plate was treated with homocysteine, both cofactor activity and thrombin-binding ability to the thrombomodulin were decreased in proportion to the concentration of homocysteine. These findings suggest that homocysteine directly inhibited the cofactor activity of thrombomodulin on endothelial cells by reducing the disulfide-bond rich epidermal growth factor-like structures of thrombomodulin. This would a result in the decrease of the antithrombotic property of endothelium and may also trigger off the synthesis of mRNA and protein of thrombomodulin to maintain the antithrombotic properties of the cells.
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PMID:An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. 131 88

A patient with an 18 year history of recurrent arterial thrombosis and no evidence of atherosclerosis or embolism of cardiac origin presented with a prolonged thrombin clotting time when performed with human thrombin. The bovine thrombin clotting time was only slightly prolonged. During 30 months of follow-up, the thrombin time fluctuated, but remained prolonged. The patient has been treated with an oral anticoagulant for the past 8 years, with no thrombotic recurrence. The inhibitor activity was due to the presence of polyclonal IgGs which bound to thrombin-Sepharose. The influence of IgGs purified from the patient's serum was compared to the influence of normal IgGs in several systems exploring the catalytic activity of thrombin and the binding of the enzyme to macromolecular substrates through secondary binding site(s). We found that the IgGs did not impair the catalytic activity toward small synthetic substrates, but inhibited the binding of thrombin to fibrinogen, thrombomodulin and heparin cofactor II. Such proteins are known to require a secondary binding site of thrombin to interact with the enzyme. The anti-thrombin antibody might have resulted from an abnormal generation of thrombin. This would be the consequence of the process favouring thrombosis. Alternatively, the autoantibody might have favoured thrombosis primarily, by impairing natural antithrombotic mechanisms triggered by thrombin.
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PMID:Partial characterization of an autoantibody recognizing the secondary binding site(s) of thrombin in a patient with recurrent spontaneous arterial thrombosis. 132 Mar

Several pieces of evidence suggest that vascular endothelium may be a site of latent herpetic viral infection, and that activation of such infection might cause or aggravate atherosclerosis. The present studies which utilized HSV-1 infection of cultured endothelial monolayers, provide insights into two phenomena seemingly relevant in considerations of atherosclerosis. Thus, mechanisms are reported by which infected endothelium may be damaged by marginated inflammatory cells, and be transformed from an anticoagulant to a procoagulant tissue. First, granulocytes are attracted to, and avidly bind, endothelium infected for very brief periods. This interaction is associated with denudation of intact cells as well as actual cytolysis through release of PMN proteases and toxic oxygen species. Second, several potentially additive abnormalities of HSV-infected endothelium would seem to foster coagulation. These include: a) its loss of surface heparans and thrombomodulin; b) its inability to synthesize prostacyclin with associated incapacity to deter platelet adhesion; c) its disordered membrane lipid conformation which is likely associated with excessive surface thrombin generation; and d) its unique ability to generate and release tissue factor. We speculate that mechanical abrasion may reactivate latent herpes (HSV or CMV) infection in endothelial cells particularly those exposed to high shear forces--for instance, at vessel bifurcations. This may underlie the endothelial damage, clotting and atheroma formation commonly found at these sites.
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PMID:Herpes virus infection of endothelium: new insights into atherosclerosis. 132 3

We have previously demonstrated that human aortic endothelium exhibits morphologic heterogeneity in situ, and this heterogeneity can be reproduced in culture. In this study, we have compared prothrombotic properties of cultured endothelial cells (EC) from areas of human aorta at high risk for atherosclerosis (HP-EC) with EC from areas at low risk (LP-EC). Using paired cultures from the same donors, we have found that the expression of cell surface thrombomodulin (TM)--as measured by the ability to generate activated protein C (APC) from protein C in the presence of thrombin--is relatively reduced on HP-EC compared to LP-EC (respectively, 4.98 +/- 4.43 vs. 5.83 +/- 4.37 pM APC/min/cm2; p = .03, n = 12). Furthermore, HP-EC more efficiently assemble the prothrombinase complex on their cellular surface, resulting in an increased rate of thrombin generation from prothrombin (9.81 +/- 3.10 (HP-EC) vs. 7.96 +/- 3.20 nM thrombin/min/cm2 (LP-EC); p less than .03, n = 7). The combination of reduced TM expression and increased prothrombinase complex assembly on HP-EC suggests a prothrombotic phenotype in these cells. These findings may be important in the pathogenesis of thrombosis associated with atherosclerotic plaques.
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PMID:Prothrombotic phenotype diversity of human aortic endothelial cells in culture. 133 14

A 29-year-old man with congenital protein C deficiency and acute myocardial infarction is reported. Four hours after the onset of chest pain, he was treated intravenously with tissue-type plasminogen activator. Subsequent coronary angiography revealed only slight stenosis of the left anterior descending coronary artery without any atherosclerosis. The propositus, his brother, and his mother, showed low levels of both protein C activity and antigen, while plasma thrombomodulin levels were normal. His grandfather had died from acute myocardial infarction at 38 years of age. We investigated several other risk factors for arterial thrombosis, including factor VII, fibrinogen, heparin cofactor II, lipoprotein (a), and anticardiolipin antibodies. No other haemostatic abnormalities apart from factor VII hyperactivity were detected in this family. To study the effects of protein C and factor VII on procoagulant activity, prothrombin time was measured after the addition of activated protein C and factor VII to protein C-deficient plasma. The prothrombin time ratio decreased along with an increase in the factor VII level. It also decreased with a decrease in the activated protein C level. These findings indicated that the procoagulant activity of factor VII was enhanced by low protein C levels, suggesting that concomitant factor VII hyperactivity may cause acute myocardial infarction in patients with protein C deficiency.
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PMID:Congenital protein C deficiency and myocardial infarction:concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis. 144 May 17

Smooth muscle cell (SMC) proliferation is a poorly understood process that plays a critical role in several pathological states, including atherosclerosis and hypertension. Recent work suggests that the oncogene c-myb and myosin, a ubiquitous cytoskeletal protein, may be directly involved in this process. We have used antisense nonmuscle myosin heavy chain (NMMHC) or c-myb phosphorothiolate oligonucleotides to inhibit proliferation of SMCs in vitro. The suppression of growth is accompanied by reductions in the concentrations of NMMHC and c-myb mRNAs as well as decreases in the levels of the corresponding proteins. The specificity of the antiproliferative effect is underscored by the absence of any detectable growth inhibition with sense NMMHC or c-myb phosphorothiolate oligonucleotides, an antisense c-myb mismatch phosphorothiolate oligonucleotide, or an antisense thrombomodulin phosphorothiolate oligonucleotide. Furthermore, the treatment of SMCs with antisense phosphorothiolate oligonucleotides for as little as 2 hours causes maximal inhibition of cell growth over the next 72 hours. Under these conditions, SMCs attain normal rates of growth over the following 48 hours, which shows that proliferation is suppressed in a reversible fashion by antisense phosphorothiolate oligonucleotides. These experiments indicate that both c-myb and nonmuscle myosin play critical roles in SMC proliferation and that reductions of either mRNA by antisense phosphorothiolate oligonucleotides arrest the process.
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PMID:Antisense nonmuscle myosin heavy chain and c-myb oligonucleotides suppress smooth muscle cell proliferation in vitro. 155 Dec 7

We have studied the procoagulant activity (PCA) of blood and spleen mononuclear phagocytes and the thrombomodulin activity of aortic segments in rabbits fed an atherogenic diet for 6 weeks as compared to rabbits fed a standard diet. Blood monocytes expressed negligible basal PCA (i.e., PCA measured immediately after cell isolation) both in treated and control rabbits. PCA induced by endotoxin in vitro was not different in the two groups. In contrast, dietary treatment resulted in a significant increase in the basal PCA of spleen cells (p less than 0.01). Moreover, the latter produced significantly more PCA than control cells (p less than 0.002) in response to endotoxin in vitro. The thrombomodulin activity associated with aortic endothelium was not different in the two groups of animals despite the presence of visible fatty streaks on the aortic endothelium of treated rabbits. When rabbits were given a single injection of endotoxin, spleen mononuclear phagocytes harvested 60 min after the injection from treated animals expressed three times more PCA (p less than 0.01) than did cells from controls. In all instances PCA was identified as tissue factor. Endotoxin injection did not affect the thrombomodulin activity of thoracic aorta from both control and diet groups. It is suggested that dietary fats may cause early functional changes in mononuclear phagocytes that lead to an increased PCA production both in vivo and in vitro. These data may be relevant to an understanding of the role of monocytes-macrophages in the pathogenesis of atherosclerosis.
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PMID:Increased macrophage procoagulant activity but normal endothelial thrombomodulin in rabbits fed an atherogenic diet. 215 50

Latent infection of vascular cells with herpes-viruses may play a pathogenic role in the development of human atherosclerosis. In a previous study, we found that cultured human umbilical vein endothelial cells (HUVECs) infected with herpes simplex virus 1 (HSV-1) became procoagulant, exemplified both by their enhanced assembly of the prothrombinase complex and by their inability to reduce adhesion of platelets. We now report two further procoagulant consequences of endothelial HSV infection: loss of surface thrombomodulin (TM) activity and induction of synthesis of tissue factor. Within 4 hr of infection of HUVECs, TM activity measured by thrombin-dependent protein C activation declined 21 +/- 3% (P less than 0.05) and by 18 hr, 48 +/- 5% (P less than 0.001). Similar significant TM decrements accompanied infection of bovine aortic endothelial cells. Identical TM loss was induced with HSV-2 infection but not with adenovirus infection. Decreased surface expression of TM antigen (measured by the specific binding of a polyclonal antibody to bovine TM) closely paralleled the loss of TM activity. As examined by Northern blotting, these losses apparently reflected rapid onset (within 4 hr of HSV infection) loss of mRNA for TM. In contrast, HSV infection induced a viral-dose-dependent increase in synthesis of tissue factor protein, adding to the procoagulant state. The results indicate that loss of endothelial protein-synthetic capacity is not a universal effect of HSV infection. We suggest that the procoagulant state induced by reduction in TM activity and amplified tissue factor activity accompanying HSV infection of endothelium could contribute to deposition of thrombi on atherosclerotic plaques and to the "coagulant-necrosis" state that characterizes HSV-infected mucocutaneous lesions.
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PMID:Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. 216 19

Significant advances have been made in our understanding of the role of the vascular endothelium in preventing thrombosis and in decreasing vascular spasm. The endothelium provides a surface receptor, thrombomodulin, that binds thrombin. In this form, thrombin loses its ability to clot fibrinogen or to aggregate platelets, but is able to activate protein C. In its activated state, protein C is able to act as an inhibitor of coagulation by virtue of its proteolytic destruction of Factors Va and VIIIa. Congenital deficiency of protein C is associated with early and recurrent thrombosis. The discovery that the endothelium is responsible for the production of a short-acting inhibitor of smooth-muscle contraction (EDRF) was a remarkable advance. One of the EDRF substances has been demonstrated to be NO, which has inhibitory effects on both smooth muscle and blood platelets. Activity of EDRF appears to be diminished or lost as a consequence of atherosclerosis, and stimuli that cause vasodilation via the EDRF pathway in normal vessels cause vasoconstriction in atherosclerotic arteries. Regression of atherosclerosis in experimental animals appears to be associated with restoration of EDRF activity.
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PMID:The endothelium, platelets, and coronary vasospasm. 264 64

To assess the risk factors for atherosclerosis in Werner's syndrome (WS), coagulation/fibrinolytic system parameters and lipid levels were investigated in 9 non-smoker patients with WS and compared with normal control values (N). The levels of thrombin antithrombin III complex (p < 0.05), D-dimer (p < 0.05), tissue plasminogen activator (p < 0.005) and PA inhibitor 1 (p < 0.01) were significantly increased, while the level of thrombomodulin (p < 0.005) in the fasting plasma was significantly decreased in the WS cases compared with N. Lipid profiles confirmed that 8 of the 9 patients were of hyperlipidemia type IIb, 7 had hyperinsulinemia and 5 fulfilled the criteria for clinical diabetes mellitus. The hypercoagulable condition suggested the existence of multiple risk factors for atherosclerosis in WS in addition to the previously reported hyperinsulinemia and hyperlipidemia.
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PMID:Hypercoagulable state indicates an additional risk factor for atherosclerosis in Werner's syndrome. 749 61


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