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 importance of lipoproteins in the etiology of atherosclerosis is well established. Evidence is now accumulating to implicate thrombin in the pathogenesis of atherosclerosis. We have investigated whether atherogenic lipoproteins can support thrombin generation. In the absence of platelets or endothelial cells, both very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (LDL) support assembly of the prothrombinase complex and generation of thrombin. Thrombin generation (per microgram of apolipoprotein) supported by VLDL was 19.4-fold greater than that supported by high-density lipoprotein (HDL), P < .00001, and 11.7-fold greater than that supported by LDL, P < .00001. Oxidation of LDL increased lipoprotein-supported thrombin generation 12-fold compared to unmodified LDL, P < .0001. We have shown that the phenomenon of lipoprotein-supported thrombin generation is mediated predominantly by specific phospholipids and is enhanced by oxidation of these phospholipids. The addition of vitamin E (alpha-tocopherol) markedly reduced the increase in thrombin generation observed after oxidation of LDL (822 +/- 57 v 138 +/- 47 nmol/L; P < .0001). These effects suggest that lipoproteins are important in the production of thrombin and that vitamin E may confer protection from the detrimental effects of lipoprotein oxidation by limiting thrombin formation. These results suggest that atherogenic lipoproteins are linked to the development of atherosclerosis in part by their capacity to support thrombin generation.
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PMID:Atherogenic lipoproteins support assembly of the prothrombinase complex and thrombin generation: modulation by oxidation and vitamin E. 942 4

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

Blood coagulation factor VIII (fVIII) in its nonactivated form circulates in plasma in a complex with von Willebrand factor (vWf). Upon activation by thrombin- or factor Xa-mediated site-specific proteolysis, activated fVIII (fVIIIa) serves as a cofactor for factor IXa. This protein complex assembled on a phospholipid surface (factor Xase) activates factor X. This complex plays the key role in the intrinsic pathway of blood coagulation. We reviewed the molecular events triggered by fVIII activation, which are required for the assembly and functioning of the Xase complex, including fVIIIa dissociation from vWf and a significant increase of fVIII affinity for binding to the phospholipid surface. Both events are mediated by activation-related cleavage within fVIII light chain (LCh), releasing the 40 amino-acid N-terminal LCh peptide, which is followed by a conformational change within the C2 domain. The conformational change within LCh is also required for the optimal fVIII cofactor functioning within the factor Xase complex, exerted via fVIIIa interactions with phospholipid, factor IXa, and factor X. Since factor IXa not only stabilizes but also proteolytically inactivates fVIIIa within the factor Xase complex, the stability of the membrane-bound fVIIIa in the presence and absence of factor IXa is discussed. In conclusion, we outline some new possible directions of the research. One of them arises from the recently demonstrated ability of plasma lipoproteins to provide a phospholipid surface for the assembly of the factor Xase complex in vitro. This finding raises a possibility that lipoproteins participate in factor Xase functioning in vivo and suggests a direct link between elevated levels of lipoproteins associated with atherosclerosis and increased thrombogenicity associated with this disease.
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PMID:Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex. 1088 49

Thrombosis is the major mechanism underlying acute complications of atherosclerosis. Although thrombogenicity of atherosclerotic plaques has been ascribed to activation of the extrinsic pathway of blood coagulation, in the present study we investigated contribution of the intrinsic factor VIII (fVIII)-dependent pathway. We found that in vitro exposure of human macrophages and smooth muscle cells (SMCs) to atherogenic oxidized low-density lipoprotein (oxLDL) enhances their ability to support activity of 2 major complexes of the intrinsic pathway, Xase and prothrombinase, leading to a 20- and 10-fold increase in thrombin formation, respectively. In contrast, human aortic endothelial cells were less responsive to oxLDL. The increase in the intrinsic procoagulant activity was related to formation of additional fVIII binding sites due to enhanced translocation of phosphatidylserine to the outer surface of oxLDL-treated cells and a 5-fold higher affinity of interaction between components of the Xase complex, activated factors VIII and IX. Processes occurring at early apoptotic stages, including changes in the cell membrane induced by free radicals, may be related to activation of the intrinsic pathway as suggested by effects of inhibitors of early apoptosis on thrombin formation. Immunohistochemical studies on human atherectomy specimens revealed the presence of fVIII in the vicinity of macrophages and SMCs in atheromatous regions with massive deposits of oxLDL, supporting the possible involvement of the intrinsic pathway in thrombus formation in vivo. Our data predict that the intrinsic pathway significantly enhances thrombogenicity of atherosclerotic lesions after removal of the endothelial layer and exposure of SMCs and macrophages to blood flow.
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PMID:Intrinsic pathway of blood coagulation contributes to thrombogenicity of atherosclerotic plaque. 1203 78

To improve the understanding of the biological functions and pharmacology of heparin and dermatan sulfate, low-molecular-weight heparin (LMWH) and low-molecular-weight dermatan sulfate (LMWDS) were labeled with tyramine (T) by covalently linking T to the terminal residue of 2,5-anhydromannose (or 2,5-anhydrotalose for dermatan sulfate). The covalent labeling was demonstrated by nuclear magnetic resonance spectroscopy. The tyramine-labeled LMWH (LMWH-T) was also labeled with fluorescein (F) by further reacting it with fluorescein isothiocyanate. The fluoresceinated LMWH-T (LMWH-T,F ) was used to analyze biological functions on blood coagulation and binding to leukocytes. The biological activities on factor Xa and thrombin inhibition remained unchanged compared with the parent compound. Flow cytometric analysis of leukocytes demonstrated binding of the modified heparin to granulocytes, monocytes, and lymphocytes, the half-live being twice as long as the antifactor Xa activity. F-labeled heparin was displaced by unlabeled heparin from all three populations of leukocytes. Binding of heparin to leukocytes may play an important role in inflammation and atherosclerosis.
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PMID:Low-molecular-weight heparin and dermatan sulfate end group-labeled with tyramine and fluorescein. Biochemical and biological characterization of the fluorescent-labeled heparin derivative. 1224 81

Coronary heart disease (CHD) is the leading cause of mortality and morbidity in the United States. Currently, there are approximately 12 million Americans with CHD, which is most frequently caused by atherosclerosis. The thrombotic complications of atherosclerosis, such as acute coronary syndrome and ischemic stroke, can be fatal and those who survive such events have a far greater risk of future cardiovascular events. This huge medical need cries out for improved novel anticoagulants, antiplatelet agents, and profibrinolytic agents. These agents will successfully respond to the medical need by providing safe, effective, and easily administered treatments that have little, if any, drug and food interactions and that require minimal monitoring. The currently approved antiplatelet agent, clopidogrel, has satisfied some of these requirements and has played a large role in expanding the antithrombotic market over the past few years. New antithrombotics approaching the marketplace, such as the prodrug thrombin inhibitor ximelagatran, have promise in expanding the antithrombotic market further. Over the past two decades, the pharmaceutical industry has mounted a huge effort to develop antithrombotics that function by inhibiting key enzymes positioned at "higher" levels of the coagulation system. Direct inhibitors of factor Xa, which may provide a better safety and efficacy profile than currently available agents, appear to be the next major class of antithrombotic agents poised to take the pharmaceutical industry one step closer to delivering the ideal antithrombotic agent. This review focuses on recent innovations in the discovery and development of potent parenteral and oral direct factor Xa inhibitors.
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PMID:Recent advances in the discovery and development of direct coagulation factor Xa inhibitors. 1452 95

The normal hemostatic process is initiated by disruption in the vascular continuity and exposure of the subendothelial components. Platelets adhere to subendothelium-bound von Willebrand factor via glycoprotein (GP) Ib complex. This initial interaction per se and the release of platelet agonists transduce signals that lead to the rise in intracellular Ca(2+). The rise in Ca(2+) induces shape change, prostaglandin synthesis, release of granular contents and conformational changes in platelet Gp IIb-IIIa. Gp IIb-IIIa in activated platelets becomes competent to bind fibrinogen and other adhesive proteins and mediates platelet cohesion (primary hemostatic plug). Furthermore, the activated platelet surface provides an efficient catalytic surface for the coagulation reactions, ultimately resulting in the formation of fibrin (secondary hemostasis). Normally the hemostatic process plays a delicate balance between keeping the blood in the fluid state to maintain flow and rapidly forming an occluding plug following vessel injury. Thrombosis occurs because of alteration in this delicate balance. Consequences of thrombosis are a major cause of morbidity and mortality in industrialized countries. Arterial thrombosis occurs in the setting of previous vessel wall injury mostly because of atherosclerosis, while venous thrombosis occurs in areas of stasis. The recent advances in our understanding of the hemostatic process have led to a better elucidation of the mechanism of action of many antithrombotic drugs and identification of new targets for drug development. The molecular target of the well known antiplatelet drug ticlopidine has been identified. Large numbers of IIb-IIIa inhibitors have been developed based on the crystal structure of a potent antagonist echistatin. The mechanism of action of heparin has been defined at the molecular level. As a result a synthetic pentasaccharide, based on antithrombin-binding domain of heparin, has been developed and tested successfully in clinical trials. New generation direct thrombin inhibitors are being developed based on the crystal structure of thrombin. Factor Xa has a critical position at the convergence of intrinsic and extrinsic pathway ways. The clinical tolerability and the efficacy of low molecular weight heparins led to the concept that inhibition of further thrombin generation, by blocking factor Xa alone, can be an effective way of preventing thrombus growth without inactivating thrombin. A large number of specific factor Xa inhibitors are under development. Some of these drugs have already undergone preliminary clinical trials and appear to be promising. Future clinical trials will determine whether these new drugs will provide better risk-benefit ratio in treatment of thrombotic disorders.
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PMID:New targets for antithrombotic drugs. 1472 68

Tissue factor (TF) plays an important role in hemostasis, inflammation, angiogenesis, and the pathophysiology of atherosclerosis and cancer. In this article we uncover a mechanism in which protein S, which is well known as the cofactor of activated protein C, specifically inhibits TF activity by promoting the interaction between full-length TF pathway inhibitor (TFPI) and factor Xa (FXa). The stimulatory effect of protein S on FXa inhibition by TFPI is caused by a 10-fold reduction of the K(i) of the FXa/TFPI complex, which decreased from 4.4 nM in the absence of protein S to 0.5 nM in the presence of protein S. This decrease in K(i) not only results in an acceleration of the feedback inhibition of the TF-mediated coagulation pathway, but it also brings the TFPI concentration necessary for effective FXa inhibition well within range of the concentration of TFPI in plasma. This mechanism changes the concept of regulation of TF-induced thrombin formation in plasma and demonstrates that protein S and TFPI act in concert in the inhibition of TF activity. Our data suggest that protein S deficiency not only increases the risk of thrombosis by impairing the protein C system but also by reducing the ability of TFPI to down-regulate the extrinsic coagulation pathway.
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PMID:Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. 1648 80

Cardiovascular disease is the leading cause for mortality and morbidity in the western world. Arterial thrombosis has multiple origins and may present with different clinical presentations such as acute coronary syndromes, stroke, and peripheral embolization. Furthermore, thrombotic complications may occur during percutaneous interventions. The underlying causes range from atherosclerosis with plaque rupture or erosion, embolization, stasis and hypercoagulable states. Thrombotic complications lead to activation of the intrinsic coagulation system and to platelet aggregation. Despite the development of effective platelet inhibitors, there is still the need for an optimal anticoagulation regimen. While unfractionated heparin is the most commonly used antithrombotic agent, which has major inherent limitations. Direct thrombin inhibitors and anti factor Xa agents are agents which may overcome the limitation of unfractionated heparin. The potential advantages of these new compounds are discussed on the basis of available clinical data in patients with coronary artery disease.
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PMID:Thrombin inhibitors and anti-factor Xa agents in the treatment of arterial occlusion. 1707 89

In this study we examined the ability of tissue factor (TF) alone, or in conjunction with factor VIIa, factor Xa and TFPI in activating a number of key signalling pathways associated with cellular growth, stress and differentiation responses in human endothelial cells. We used luciferase reporter systems to demonstrate the activation of p42/44 MAPK by the TF-FVIIa complex, mediated via the PAR1 receptor. TF alone was capable of interacting with the cell surface and was sufficient to activate the JNK-SAPK pathway and subsequently AP-1, but the level of activation was enhanced by the activity of FXa on PAR1 and 2. Furthermore, the phosphorylated form of the transmembrane-cytoplasmic domain of TF was directly responsible for activation of these pathways. CREB activation occurred in response to TF-FVIIa in a non-protease dependent manner but was lowered on addition of FXa. Finally, NFkappaB activation occurred in response to FVIIa or FXa, with the latter exhibiting higher levels of activation. In conclusion, we have shown that TF is capable of activating differing signalling pathways, via more than one mechanism. The differential influence of TF is modified depending on the presence of other coagulation factors and ultimately acts as a deciding factor in the determination of cellular fate.
Atherosclerosis 2007 Sep
PMID:Differential functions of tissue factor in the trans-activation of cellular signalling pathways. 1713 81


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