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)

Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE(-/-)) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE(-/-) mice and mice doubly deficient for apoE and PAI-1 (PAI-1(-/-)/apoE(-/-)). Consistent with a previous report, PAI-1(+/+)/apoE(-/-)and PAI-1(-/-)/apoE(-/-) mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow. (Blood. 2000;96:4212-4215)
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PMID:Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. 1111 Jun 93

The influence of thyroid failure on haemostasis is controversial, both hypocoagulable and hypercoagulable states have been reported. Since both subclinical and overt hypothyroidism have been associated with atherosclerosis, a hypercoagulable state in addition might represent a risk factor for thromboembolic disease. We investigated various haemostatic variables in 42 women with subclinical hypothyroidism and compared them to 66 euthyroid controls. Prothrombin time, activated partial thromboplastin time, fibrinogen, factor VII activity (FVII:C), factor VII antigen (FVII:Ag), factor VIII activity, von Willebrand factor (vWF), antithrombin III, heparin cofactor II, protein C, protein S, plasminogen, antiplasmin, plasminogen activator inhibitor and tissue plasminogen activator, as well as common lipid variables, were measured. Factor VII:C (P < 0.02) and the ratio FVII:C/FVII:Ag (P < 0.01) were significantly increased in subclinical hypothyroid patients compared to the control group. Both parameters remained higher in hypothyroid patients after exclusion of 18 women on oestrogen replacement therapy. No differences were found between the groups with respect to vWF or the other haemostatic and lipid variables tested. Patients with subclinical hypothyroidism had significantly higher levels of FVII:C. The greater increase in FVII:C compared to that of FVII:Ag, as shown by the increase in their ratio, might reflect the presence of activated FVIIa. This might mean a hypercoagulable state, which could contribute to the increased prevalence of coronary heart disease reported in such patients. A hypercoagulable state might be another argument in favour of thyroxine replacement treatment in subclinical hypothyroidism, especially in patients with additional risk factors for vascular disease.
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PMID:Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease. 1116 51

Fibrinolytic activity has been reported to be decreased in atherosclerosis. Recently, annexin II was identified as a coreceptor on endothelial cells for plasminogen and tissue plasminogen activator. In this study, we examined whether recombinant annexin II (rAN II) protein can modulate fibrinolytic activity on vascular endothelium in vitro and in vivo. The effect of rAN II on human umbilical vein endothelial cells (HUVECs) was measured. Addition of a fluorescent plasmin substrate revealed that HUVECs treated with rAN II exhibited significantly more plasmin generation than those treated with BSA. Moreover, rAN II treatment of HUVECs restored plasmin generation impaired by plasminogen activator inhibitor-1 or homocysteine pretreatment. In a rat carotid artery thrombus model, the patency of thrombosed carotid arteries was significantly enhanced by rAN II injection, in contrast to BSA injection, without systemic blood coagulation dysregulation. We found that rAN II enhanced plasmin generation on vascular endothelium in vitro and reduced thrombus formation in vivo, and concluded that enhancement of endothelial fibrinolytic activity by annexin II could modulate the hypercoagulable state of atherosclerosis. Further study of rAN II in vitro and in vivo may lead to the establishment of novel therapeutic approaches to thrombogenic vascular disease.
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PMID:Recombinant annexin II modulates impaired fibrinolytic activity in vitro and in rat carotid artery. 1173 91

Expression analysis and epidemiologic studies have provided indirect evidence that proteinases and growth factors play a role in the development of atherosclerosis and complications such as aneurysm formation and plaque rupture. Studies using genetically altered mice have proven to be an elegant tool to study the causal involvement of these factors in atherogenesis and to gain insight into the underlying mechanisms. Recently, proteinases of the plasminogen and matrix metalloproteinase (MMP) systems as well as their inhibitors have received much attention, and these studies together have emphasized the complexity of their role in vascular disease. This overview summarizes the current knowledge on plasminogen activator inhibitor-1 (PAI-1) in the progression of atherosclerosis and the influence of MMPs in aneurysm formation. In addition, a possible role for Gas6, the product of growth arrest-specific gene 6, in atherosclerotic lesion development is put into perspective.
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PMID:Genetic studies on the role of proteinases and growth factors in atherosclerosis and aneurysm formation. 1179 60

The accumulation of fibrillar amyloid-beta protein (A beta) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), is a key pathological feature of Alzheimer's disease and certain related disorders and is intimately associated with cerebrovascular cell death both in vivo and in vitro. Moreover, severe CAA leads to loss of vessel wall integrity and cerebral hemorrhage. Although the basis for these latter pathological consequences in CAA remains unresolved alterations in local proteolytic mechanisms may be involved. Here we show that pathogenic forms of A beta stimulate the expression of plasminogen activator activity in cultured human cerebrovascular smooth muscle (HCSM) cells, an in vitro model of CAA. RNase protection assays and plasminogen zymography showed that urokinase-type plasminogen activator (uPA) was responsible for this activity. There was preferential accumulation of uPA on the HCSM cell surface that was mediated through a concomitant increase in expression of the uPA receptor. In the presence of plasminogen there was robust degradation of A beta that was added to the HCSM cells resulting in restoration of cell viability. This suggests that increased expression of uPA may initially serve as a protective mechanism leading to localized degradation and clearance of the pathogenic stimulus A beta. On the other hand, chronic expression of uPA and plasminogen activation led to a profound loss of HCSM cell attachment. This suggests that a similar prolonged effect in vivo in the cerebral vessel wall may contribute to loss of integrity and cerebral hemorrhage in CAA.
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PMID:Amyloid beta-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells. 1275 71

The aims of neurology in Japan in the 21st Century should include establishment of therapeutic measures for neurological diseases, training clinical neurologists to cover both static and dynamic aspects of neurology, and application of gene therapy and neurogenesis to clinical neurology. It is also important to note that once any neurological disease develops, remaining sequelae are usually not curable, so the problem of how to prevent the onset of neurological diseases, that is preventive neurology, will become increasingly important. The key target for prevention in neurology is cerebro-vascular disease, since it is very common. Many risk factors are known for ischemic CVD. However, even for the management of hypertension, the so-called number needed to treat (NNT) is 29-118/5 years for primary prevention and 14-23/5 years for secondary prevention. It is also important to consider genetic factors that influence CVD, including abnormal plasminogen, Lp (a), ACT Isehara 1 gene, apolipoprotein E and so on, since these congenital factors reinforce known acquired risk factors, such as hypertension. In addition, the presence of asymptomatic cerebral infarction, as well as PVH and DSWMH, in MRI T2-weighted images is an important predictor of future symptomatic CVD. Finally, storage of one's own bone marrow cells might be useful, since in the event of onset of CVD, dementia or other neurological diseases, autotransplantation with cytokine might become available for neurogenesis. The results of our recent experiments indicate that this idea may be feasible.
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PMID:[Neurology in the 21st century--the era of preventive neurology utilizing new diagnostic and therapeutic techniques]. 1515 50

Fibrinolysis plays a crucial role in the development of vascular disease. The interface between the plasminogen activators and inhibitors determines the fibrinolytic potential of human blood. In addition to fibrin degradation, fibrinolytic system components modulate several complex biological events such as angiogenesis, tumorigenesis, arteriosclerosis and cellular migration. Recent experimental and clinical data indicated that PAI-1 as a novel vascular risk factor. In this concise review, we will examine the accumulating evidence suggesting that there is an intricate relationship between these systems which may provide new therapeutic strategies for prevention of vascular disease.
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PMID:Pivotal role of plasminogen-activator inhibitor 1 in vascular disease. 1570 73

Lipoprotein(a) and total plasma homocysteine levels are now established as independent atherothrombogenic risk factors. A distinctive pathophysiological feature of lipoprotein(a) is its antifibrinolytic activity, an effect dependent on plasma concentration and high affinity for fibrin of its small size apo(a) component. A stimulating effect of homocysteine on purified lipoprotein(a) has been proposed. However, little is known about their specific interactions in human plasma. We demonstrate by immunochemical, ligand-binding and plasminogen activation studies, that homocysteine modifies the structure and function of lipoprotein(a) in human plasma; it reduces the apo(a)/apoB disulfide bond causing the appearance of free apo(a) with high affinity for fibrin that inhibits plasminogen binding and plasmin formation (r= -0.995, p =0.002). These effects were evident particularly in plasma samples containing lipoprotein(a) with low affinity for fibrin and more than 22 kringles apo(a) isoforms. In contrast, for plasmas containing high fibrin affinity lipoprotein(a) (less than 22 kringles apo[a] isoforms) no significant change neither in fibrin binding nor in plasmin formation was observed. Furthermore, isolated apo(a) recombinants (10 to 34 kringles) that have been shown to display size-independent high affinity for fibrin were not affected by homocysteine, thus confirming lipoprotein(a) as its main target. These results suggest that the pro-atherogenic role already conferred to lipoprotein(a) by small apo(a) isoforms may be extended to large apo(a) isoforms if released in plasma by homocysteine, as this mechanism reveals their high fibrin affinity. Lipoprotein(a) and homocysteine may therefore constitute, if acting in concert, a new risk factor for athero-thrombotic vascular disease.
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PMID:Mechanism for the homocysteine-enhanced antifibrinolytic potential of lipoprotein(a) in human plasma. 1611 87

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.
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PMID:MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells. 1614 77

Activation of inflammatory and coagulation pathways is important in the pathogenesis of vascular disease. There is ample evidence that extensive cross-talk between these two systems exists, whereby inflammation not only leads to activation of coagulation, but coagulation also markedly affects inflammatory activity. The main interfaces linking coagulation and inflammation are the tissue factor pathway, thrombin, the protein C system and the fibrinolytic (or plasminogen-plasmin) system. Proinflammatory cytokines and chemokines can affect all these coagulation mechanisms, and vice versa, activated coagulation proteases and physiological anticoagulants or components of the plasminogen-plasmin system can modulate inflammation by specific cell receptors. The intricate relationship between inflammation and coagulation may not only be relevant for vascular thrombotic disease but also has major consequences in the pathogenesis of microvascular failure and subsequent multiple organ failure in the setting of severe infection. This review focuses on the present understanding of the bidirectional relationship between inflammation and coagulation.
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PMID:Two-way interactions between inflammation and coagulation. 1622 80


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