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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in determining anti-thrombogenic functions of vascular endothelial cells are reviewed. The following anticoagulant and fibrinolytic systems of endothelial cells are physiologically important; (1) Endothelial cell-derived metabolites including prostacyclin and nitric oxide (NO) support platelet inactivity. (2) Antithrombin III and tissue factor pathway inhibitor (TFPI) bound to heparin-like proteoglycans on endothelial cell membrane inhibit activated serine protease coagulation factors such as thrombin, factor Xa and factor VIIa-tissue factor complex. (3) Thrombomodulin converts thrombin from procoagulant into anticoagulant. Thrombin associated to thrombomodulin on endothelial cells activates protein C. Activated protein C in concert with protein S bound to endothelial cell membrane inactivates factors Va and VIIIa. (4) A receptor for both tissue plasminogen activator and plasminogen on endothelial cells provides an efficient plasmin generating system. Perturbation of these anti-thrombogenic systems of endothelial cells is caused by endotoxin (LPS), cytokines such as interleukin-1 and tumor necrosis factor (TNF), and risk factors for atherogenesis including lipoprotein(a) and homocysteine may result in arterial or venous thrombosis with subsequent development of atherosclerosis.
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PMID:[Anticoagulant and fibrinolytic systems of the injured vascular endothelial cells]. 817 40

The study of vascular cell function and the interactions of endothelial cells (EC), smooth muscle cells (SMC), and monocyte-derived macrophages has expanded greatly during the past 20 years, and the resultant information has reformed our views on the genesis of atherosclerotic plaque. The concept of an activated or injured endothelium that exhibits properties distinct from healthy adult endothelium is now well accepted. Activated EC may exhibit proatherogenic behavior, including increased leukocyte adhesivity, procoagulant activity, and SMC mitogen production. Thrombin, a coagulation-system protease, may serve as a physiologic activator of EC. Thrombin at sites of vascular injury may stimulate diverse functions, including increased expression of monocyte adhesion proteins and platelet-derived growth factor (PDGF). The monocyte-derived macrophage has been implicated as a participant in several aspects of atherosclerotic plaque development. The attachment of monocytes to EC is the initial event in the interaction of these cells with the vessel wall. Distinctly focal adhesion of monocytes to EC of large vessels is one of the earliest documented events in experimentally induced atherosclerosis and, thus, regulation of this process may be critical to the development of the disease. Intimal proliferation of SMC is another hallmark of the atherosclerotic lesion. Platelet-derived growth factor is both a chemoattractant and mitogen for SMC. Therefore, if EC secrete PDGF abluminally, both the migration of SMC into the intima and subsequent proliferation will be stimulated. Immunocytochemistry and insitu hybridization have verified that vascular EC express PDGF mRNA and protein in vivo under certain conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular mechanisms of atherogenesis. 829 38

It is increasingly realised that fibrin deposition and fibrin lysis are major factors in vascular pathology. In addition to thrombotic occlusion fibrin is a component of atherosclerotic lesions, but the increased interest in components of the haemostatic system was mainly triggered by clinical use of fribrinolytic agents, and the problems of re-stenosis following angioplasty. This review focuses on the main components of the fibrinolytic system--tissue plasminogen activator (tPA), urokinase (uPA) and plasminogen activator inhibitor (PAI-1)--and on thrombin. These factors are not only involved in fluid phase clotting and clot lysis; they react specifically with cells and matrix components. During the last 5 years, the main period under review, there have been numerous studies on their interactions with endothelial and smooth muscle cells in culture, in whole tissues and in vivo, and with arterial extracellular matrix of which a major component is fibrin. Plasminogen activators bind to cell surface receptors, influence cell migration and release active thrombin from fibrin. Thrombin emerges as a pluripotent factor which modulates many aspects of endothelial and smooth muscle cell behaviour, including release and synthesis of fibrinolytic components, and stimulation of cell proliferation.
Atherosclerosis 1996 Aug 02
PMID:Haemostatic factors and atherogenesis. 883 Sep 27

Thrombin's proteolytically activated "tethered-ligand" receptor is widely expressed and mediates many of thrombin's actions on cells. Its central role in thrombin-stimulated human platelet activation and vascular smooth muscle proliferation as well as location in atherosclerotic plaques suggests receptor involvement in arterial thrombosis and atherosclerosis. Thrombin receptor antagonists, should they be effective, could be more selective than thrombin active site inhibitors in antithrombotic therapy as well as other indications. Blocking antibodies to peptides derived from the thrombin receptor have been used as prototypical thrombin receptor antagonists in vitro and have been useful in implicating this receptor in thrombin's actions on a variety of cell types. These antibodies have also shown the involvement of the receptor in arterial thrombosis models in nonhuman primates. Amino acid substitution studies have shown the structural requirements for receptor activation of peptides homologous to the new NH2-terminus. Peptide-based partial agonists and antagonists have been synthesized by NH2-terminal replacements of the serine in the receptor activating peptides. Current thrombin receptor antagonists lack potency and some are partial agonists; however, it is expected that more potent compounds will result from further investigation. The potency limitations are important to overcome before serious evaluation of their efficacy can be determined.
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PMID:Thrombin receptor antagonists. 883 6

Thrombin has been implicated as an important mediator of vascular lesion formation in atherosclerosis and restenosis. To investigate a potential role for thrombin signaling in the vascular response to hypertension, we have studied thrombin receptor (TR) expression and regulation in hypertensive rats. Aortic TR mRNA was upregulated by angiotensin II (Ang II)-induced hypertension (10.7 +/- 2.5 times control, P < .02), which correlated with a 4-fold increase in thrombin-induced constriction in isolated endothelium-denuded aortic rings. The AT1 receptor antagonist losartan normalized blood pressure and TR mRNA. Conversely, lowering blood pressure to the same degree with hydralazine did not abolish the upregulation of TR mRNA expression. When low-renin low-Ang II hypertension was induced in Dahl salt-sensitive rats, there was no detectable increase in the expression of aortic thrombin receptor mRNA. Finally, treatment with a chimeric heparin-binding form of the recombinant human Cu/Zn superoxide dismutase caused complete inhibition of TR mRNA upregulation, suggesting that an increased rate of superoxide anion production is an important signaling mechanism. Thus, increased TR expression via a redox-sensitive mechanism in the aortic smooth muscle of rats treated with Ang II represents a novel in vivo mechanism through which the hypertensive effects of Ang II are mediated.
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PMID:Vascular thrombin receptor regulation in hypertensive rats. 916 86

We investigated the role of thrombin in the pathogenesis in atherosclerosis and restenosis. First we examined the effect of thrombin on cultured human vascular smooth muscle cells (VSMC). We showed that thrombin acts as a mitogen on VSMC through thrombin receptor. The expression of thrombin receptor was increased in the cell lines of VSMC established from directional coronary atherectomy (DCA). This is more pronounced in the cells from patients with restenosis after PTCA. Next we investigated the signaling pathway from thrombin/thrombin receptor. Thrombin activates thrombin receptor resulting in the exposing of the agonist peptide domain (thrombin receptor agonist peptide, TRAP). The signal from thrombin/thrombin receptor activated protein C kinase, tyrosine kinase, and MAP kinase and resulted in NF-kappa B activation. Furthermore, treatment of the cells with antisense p65 oligodeoxynucleotides of NF-kappa B inhibited the thrombin-stimulated growth of VSMC in vitro. These results suggest that thrombin may have a role in the pathogenesis of atherosclerosis and restenosis after PTCA through the thrombin receptor.
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PMID:Thrombin activates NF-kappa B through thrombin receptor and results in proliferation of vascular smooth muscle cells: role of thrombin in atherosclerosis and restenosis. 918 20

Air desiccation endothelial injury followed by cholesterol feeding is known to induce focal femoral atherosclerosis in rabbits. We previously demonstrated the effectiveness of hirudin in limiting restenosis after balloon angioplasty (BA) in this double instrumentation injury (DI) model. In the present study, we sought to determine whether BA without prior air desiccation endothelial injury (single instrumentation injury (SI)) would lead to similar femoral lesions, and whether the response to this injury might also be limited by hirudin. Accordingly, 38 femoral arteries of cholesterol-fed rabbits underwent BA with (n = 18, DI group) or without (n = 20, SI group) prior air desiccation endothelial injury. Animals were killed 24 hours or 28 days after BA. Twenty-four hours after BA, the SI group (n = 10) had a significantly smaller percentage of cross-sectional area narrowing by plaque than the DI group (n = 8) (0% versus 42% +/- 9%, p = 0.008). However, 28 days after BA, the percentages of cross-sectional area narrowing by plaque in the SI (n = 10) and DI (n = 10) groups were similar (59% +/- 6% versus 68% +/- 1%, p = NS). The percentages of intima (16% +/- 3% versus 16% +/- 3%, p = NS) and media occupied by foam cells were also similar in the two groups. To test whether hirudin administration would limit arterial narrowing after injury in the SI model, we randomly assigned cholesterol-fed rabbits that had not undergone air desiccation injury to either bolus hirudin followed by repeat dosing 24 hours after BA or bolus heparin (150 U/kg) at the time of BA. The hirudin-treated group showed significantly less angiographic and histologic restenosis 28 days after BA, despite no difference in early (0 to 72 hours) cumulative cellular proliferation between the two groups. Thus, in the cholesterol-fed rabbit, plaque formation and foam cell accumulation are similar after BA of a non-air-desiccated (SI) or focally atherosclerotic (DI) artery. Thrombin inhibition with hirudin limits arterial narrowing after SI, further emphasizing the role of thrombin in neointimal growth after injury.
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PMID:A new single-injury model of balloon angioplasty in cholesterol-fed rabbits: beneficial effect of hirudin and comparison with double-injury model. 925 84

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
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PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

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

Sudden extreme physical stress is associated with an increased risk of myocardial infarction mainly in people with preexisting atherosclerosis. In this study we compared the effect of submaximal exercise on coagulation and fibrinolysis in patients with peripheral arterial occlusive disease (PAOD) with that in healthy control subjects. Fifteen PAOD) patients with intermittent claudication and 15 healthy control subjects, matched for age, sex, medication use, smoking habit, and conditioning, were studied. Thrombin-antithrombin III complex (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1 antigens (Ag), t-PA activity, and plasmin-alpha2-antiplasmin complex (PAP), as well as plasma catecholamines, were measured before and after a treadmill exercise test. At rest, fibrinogen (3.3+/-0.5 versus 2.9+/-0.5 g/L [mean+/-SD]; P<.05), D-dimer (392+/-128 versus 271+/-113 ng/mL; P<.05), t-PA Ag (9.1+/-5.1 versus 5.5+/-1.2 ng/mL; P<.02), and PAI-1 Ag (14.9+/-7.1 versus 7.6+/-3.8 ng/mL; P<.002) levels in plasma were markedly higher in the patient group than in the control group. In patients but not in control subjects, exercise of similar intensity elevated circulating concentrations of TAT (from 3.43+/-1.45 to 4.83+/-2.27 ng/mL; P<.05). Exercise caused a parallel increase in D-dimer, t-PA Ag, t-PA activity, PAP, and catecholamines in both groups, whereas PAI-1 Ag remained stable. Plasma lactic acid was significantly higher in patients after exercise and was associated with lower-limb ischemia. Compared with healthy control subjects, patients with PAOD showed higher t-PA Ag, PAI-1 Ag, and D-dimer levels both at rest and after exercise. Notably, submaximal exercise on a treadmill enhanced thrombin formation in patients with PAOD but not in the control subjects. Sudden catecholamine release and local ischemia during exercise may accelerate the preexisting prothrombotic potential of the atherosclerotic vessel wall.
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PMID:Physical exertion induces thrombin formation and fibrin degradation in patients with peripheral atherosclerosis. 948 89


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