Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although macroangiopathies such as peripheral vascular disease (PVD), cerebral vascular disease (CVD), and coronary heart disease (CHD) can often be observed in patients with diabetes mellitus, they are not specific for diabetes mellitus. Moreover, it is unclear whether their progressive mechanism is different. In the present study, we compared the risk factors among the diabetic macrovascular complications. Univariate analyses showed that in all patients, age at examination, duration of diabetes, thrombin-antithrombin III complex (TAT) level, fibrinogen level, lipoprotein (a) (Lp(a)) level, total cholesterol (T-Chol) level, and existence of microagiopathy were risk factors for PVD. Age, duration of diabetes, insulin level, TAT level, fibrinogen level, HDL cholesterol (HDL-Chol) level, hypertension, and nephropathy were risk factors for CVD. Only fibrinogen level was a risk factor for CHD. Moreover, Lp(a) level was a risk factor for PVD and CVD in male patients, but not in females. On the other hand, insulin level was a risk factor for CVD in female patients, but not in males. Multivariate analyses showed that TAT level, T-Chol level, and neuropathy were independent variables for PVD and that age, TAT level, and HDL-Chol level were independent variables for CVD. On the other hand, only fibrinogen level was the independent variable for CHD in males. Our results suggest that the progressive mechanism of PVD and CVD might be different from that of CHD and might differ according to gender in Japanese diabetic patients.
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PMID:Comparison of risk factors of macrovascular complications. Peripheral vascular disease, cerebral vascular disease, and coronary heart disease in Japanese type 2 diabetes mellitus patients. 1112 Apr 54

Fibrinogen plays a complex role in hemostasis, thrombosis, and vascular disease. Hyperfibrinogenemia is an independent vascular risk factor and dysfibrinogenemia can provoke thrombosis. Afibrinogenemia is usually responsible for hemorrhagic diathesis, and unexpected ischemic lesions are intriguing. We report the case of an afibrinogenemic patient, who at the age of 30 developed ischemic lesions of the feet related to severe stenosis of the iliac and hypogastric arteries. The biopsy of the iliac artery lesion showed an intense myointimal hyperplasia. We performed standard hemostatic analysis and analyzed the activation markers of platelets and coagulation factors and the kinetics of thrombin generation in the patient and in normal control plasmas treated or not with reptilase. Occlusive arterial lesions were attributed to a disruptive hematoma penetrating the vascular lumen. Thrombin concentration after calcium addition increase markedly in the afibrinogenemic patient and in defibrinated normal plasma, as compared to untreated normal plasma. Thrombin-antithrombin complexes (T-AT) were markedly enhanced while F1+2 prothrombin fragments stayed in the normal range. These results suggested activation of coagulation and in vivo circulating thrombin. Thrombin activates the platelets that secrete growth factors for smooth muscle cells and generate the intimal hyperplasia. Recurrent hemorrhage within the vessel wall might induce injury and local thrombin generation. Thrombin not trapped by the clot is available for platelet activation and smooth muscle cell migration and proliferation. The absence of a protective fibrin cap on the intima might account for intima vulnerability and embolization. Afibrinogenemia appears in this paradoxical situation as a vascular risk factor.
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PMID:Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. 1136 14

Thrombin is a serine protease that potently activates platelets and catalyzes the conversion of fibrinogen to fibrin. Thrombin also exerts direct effects on vascular cells, such as smooth muscle cells, via interactions with members of the protease-activated receptor family. Evidence in several animal models implicates thrombin-mediated signaling events in the response to injury that typifies vascular lesion formation in atherosclerosis and restenosis. In this review, we examine the activation of protease-activated receptors by thrombin, the downstream signaling events mediated by these receptors, and the physiological role of thrombin in vascular cells and vascular disease.
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PMID:New tricks for old dogs: nonthrombotic effects of thrombin in vessel wall biology. 1137 67

During thrombosis, vascular wall cells are exposed to clotting factors, including the procoagulant proteases thrombin and factor Xa (FXa), both known to induce cell signaling. FXa shows dose-dependent induction of intracellular Ca(2+) transients in vascular wall cells that is active-site-dependent, Gla-domain-independent, and enhanced by FXa assembly into the prothrombinase complex. FXa signaling is independent of prothrombin activation as shown by the lack of inhibition by argatroban, hirudin and the sulfated C-terminal peptide of hirudin (Hir(54-65)(SO3(-))). This peptide binds to both proexosite I in prothrombin and exosite I in thrombin. In contrast, signaling is completely blocked by the FXa inhibitor ZK-807834 (CI-1031). No inhibition is observed by peptides which block interaction of FXa with effector cell protease 1 receptor (EPR-1), indicating that this receptor does not mediate signaling in the cells assayed. Receptor desensitization studies with thrombin or peptide agonists (PAR-1 or PAR-2) and experiments with PAR-1-blocking antibodies indicate that signaling by FXa is mediated by both PAR-1 and PAR-2. Potential pathophysiological responses to FXa include increased cell proliferation, increased production of the proinflammatory cytokine IL-6 and increased production of prothrombotic tissue factor. These cellular responses, which may complicate vascular disease, are inhibited by ZK-807834.
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PMID:FXa-induced responses in vascular wall cells are PAR-mediated and inhibited by ZK-807834. 1156 39

Cystatin C, a major extracellular cysteine proteinase inhibitor, is deposited as amyloid in brain haemorrhage patients with hereditary cystatin C amyloid angiopathy (HCCAA). A disease-causing mutation on the genetic level results in the substitution Leu68-->Gln (L68Q) in cystatin C, which causes protein instability. Besides carrying the L68Q substitution, cystatin C in amyloid deposits isolated from patients is N-terminally truncated by 10 amino acids. To elucidate the role of the N-terminal truncation for protein stability and aggregation properties, (delta1-10,L68Q)-cystatin C was produced in an Escherichia coli expression system and characterised. Unlike wild-type cystatin C, this variant rapidly dimerised under physiological conditions. Two unfolding intermediates of (delta1-10,L68Q)-cystatin C were identified, under the same pH and ionic strength conditions as required to form intermediates of full-length L68Q cystatin C. No evidence was found that the N-terminal truncation per se alters protein stability and leads to higher forms of aggregation. Monomeric as well as dimeric L68Q cystatin C incubated with neutrophil elastase was truncated as in HCCAA patients' amyloid. A protein variant with a thrombin cleavage site placed in front of residue Gly11 in L68Q cystatin C was constructed and used to confirm that the N-terminal segment is similarly accessible to proteinases in the monomeric and dimeric states of L68Q cystatin C. Thus, the N-terminal segment of L68Q cystatin C is exposed to proteolytic attack and does not seem to be involved in intramolecular contacts leading to dimerisation or higher-order aggregation. We conclude that the N-terminal truncation likely is an event secondary to amyloid formation, and of no relevance for the development of HCCAA.
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PMID:Physico-chemical properties of the N-terminally truncated L68Q cystatin C found in amyloid deposits of brain haemorrhage patients. 1193 68

There is growing evidence for a role of factor XIII (FXIII) in vascular disease. FXIII measures were determined in (i) a nested case-control study from the Second Northwick Park Heart Study of 63 men with myocardial infarction (MI) and 124 age-matched controls and (ii) in a case-control study of 475 subjects with acute stroke and 461 controls followed up for 54 months for mortality. In both studies, measures of FXIII A- and B-subunit antigen, FXIII activity and prothrombin fragments (F1 + 2) were made. An in vitro model was used to investigate the effects of thrombin activity on FXIII A- and B-subunit antigen levels. In study 1, patients clinically free of coronary artery disease who later developed MI had lower adjusted FXIII A-subunit levels at recruitment (129.2%vs 113.3%, P = 0.007). In study 2, stroke patients with large vessel disease had lower A-subunit antigen levels (102.1%vs 127.2%, P < 0.001), but higher F1 + 2 levels (0.941%vs 0.753%, P < 0.05), than subjects with small vessel disease. Levels of FXIII A-subunit (100%vs 117%, P < 0.0001) were lower and F1 + 2 higher (1.020%vs 0.702%, P < 0.0001) in stroke patients who had died compared with those still alive at the end of the follow-up period. Low concentrations of FXIII A-subunit antigen predicted vascular outcome in otherwise healthy subjects and relate to both size of infarct and poor post-stroke survival in patients with acute ischaemic stroke. Low in vitro concentrations of FXIII A-subunit antigen wererelated to increased thrombin generation and, thus, increased risk of thrombotic events.
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PMID:Factor XIII A-subunit concentration predicts outcome in stroke subjects and vascular outcome in healthy, middle-aged men. 1218 Oct 53

Thrombomodulin (TM) slows down the interaction rate between thrombin and plasminogen activator inhibitor 1 (PAI-1). We now show that the 12-fold reduced inhibition rate in the presence of TM does not result from an altered distribution between PAI-1 cleavage and irreversible complex formation. Surface plasmon resonance (SPR) revealed an over 200-fold reduced affinity of TM for thrombin-VR1tPA as compared to thrombin, demonstrating the importance of the VR1 loop in the interaction of thrombin with both TM and PAI-1. Furthermore, in contrast to ATIII, PAI-1 was not able to bind the thrombin/TM complex demonstrating complete competitive binding between PAI-1 and TM. Kinetic modeling on the inhibitory effect of TM confirms a mechanism that involves complete steric blocking of the thrombin/PAI-1 interaction. Also, it accurately decribes the biphasic inhibition profile resulting from the substantial reduction of the extremely fast rate of reversible Michaelis complex formation, which is essential for efficient inhibition of thrombin by PAI-1. Vitronectin (VN) is shown to partially relieve TM inhibitory action only by vastly increasing the initial rate of interaction between free thrombin and PAI-1. In addition, SPR established that solution-phase PAI-1/VN complexes and non-native VN (extracellular matrix form) bind TM directly via the chondroitin sulphate moiety of TM. Collectively, these results show that VR1 is a subsite of exosite 1 on thrombin's surface, which regulates exclusive binding of either PAI-1 or TM. This competition will be physiologically significant in controlling the mitogenic activity of thrombin during vascular disease.
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PMID:A steady-state competition model describes the modulating effects of thrombomodulin on thrombin inhibition by plasminogen activator inhibitor-1 in the absence and presence of vitronectin. 1270 53

Information is rapidly emerging regarding the important role of the arterial vasa vasorum in a variety of systemic vascular diseases. In addition, increasing evidence suggests that progenitor cells of bone marrow (BM) origin may contribute to postnatal neovascularization and/or vascular wall thickening that is characteristic in some forms of systemic vascular disease. Little is known regarding postnatal vasa formation and the role of BM-derived progenitor cells in the setting of pulmonary hypertension (PH). We sought to determine the effects of chronic hypoxia on the density of vasa vasorum in the pulmonary artery and to evaluate if BM-derived progenitor cells contribute to the increased vessel wall mass in a bovine model of hypoxia-induced PH. Quantitative morphometric analyses of lung tissue from normoxic and hypoxic calves revealed that hypoxia results in a dramatic expansion of the pulmonary artery adventitial vasa vasorum. Flow cytometric analysis demonstrated that cells expressing the transmembrane tyrosine kinase receptor for stem cell factor, c-kit, are mobilized from the BM in the circulation in response to hypoxia. Immunohistochemistry revealed an increase in the expression of c-kit+ cells together with vascular endothelial growth factor, fibronectin, and thrombin in the hypoxia-induced remodeled pulmonary artery vessel wall. Circulating mononuclear cells isolated from neonatal calves exposed to hypoxia were found to differentiate into endothelial and smooth muscle cell phenotypes depending on culture conditions. From these observations, we suggest that the vasa vasorum and circulating progenitor cells could be involved in vessel wall thickening in the setting of hypoxia-induced PH.
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PMID:Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. 1275 86

The term "disseminated intravascular coagulation" (DIC) defined a pathologic process which complicates the clinical course of many diseases; it is characterized by huge amounts of thrombin and plasmin within the circulation. There are a lot of causes of these intermediary mechanism of disease, among these, infections and neoplasia are the most frequent. Aortic aneurysm is a vascular disease than can be complicated with DIC. We report a case of a patient affected of chronic disseminated intravascular coagulation complicated with systemic hemorrhagic syndrome, of vascular origin (an aortic aneurysm). It was treated with a low molecular weight heparin (LMWH), but in the presence of an allergy disorder the drug was discontinued and substituted by another LMWH. The hemorrhagic complications were treated with antifibrinolytics associated to the LMWH. The drug was held up 30 months with an acceptable performance status and no significant secondary effects except osteoporosis.
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PMID:[Long-term treatment with low molecular weight heparin, of chronic disseminated intravascular coagulation]. 1276 33

Reviewing advances in cardiology and haematology together may appear at first sight to require some artificiality to make a satisfying fit. For two reasons, at least, this is not the case. Firstly, convergence in biology has become very clear over the past decade and this could not be better illustrated by the demonstration that the haemangioblast is the common progenitor of both haemapoietic stem cells and vascular endothelium. This opens the way to common (and differential) approaches to the manipulation of these cells, a field at present in its infancy. A second convergence is the common goal of understanding the processes resulting in haemostasis, thrombosis and vascular occlusion and the means for developing effective antithrombotics. This is exemplified by a number of agents either in use or in clinical trial as a result of haematological and cardiological collaboration. This collaboration is recognisable with the development, many years ago, of streptokinase and the use of aspirin in vascular disease and continues to this day with specific antiplatelet inhibitors and oral thrombin inhibitors as they become accepted into clinical use over the next few years. Here we review current advances in pharmacological treatments in cardiology and haematology, grouped primarily by disease process, focusing on novel and emerging therapies likely to be of importance in the future.
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PMID:Novel and emerging therapies in cardiology and haematology. 1276 38


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