Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.
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PMID:[Blood coagulation and fibrinolysis in arteriosclerosis]. 1041 53

While there is indisputable evidence supporting the beneficial role of aerobic exercise in reducing cardiovascular risk factors, there are few dose-response studies of this relationship. Increasingly, it is thought that the cardiovascular benefits of exercise are significantly influenced by adaptations within skeletal muscle and its vasculature. However, little is known about the molecular mechanisms underlying these adaptations. To address this need, we initiated a study utilizing longitudinal, microarray-based gene expression profiling of serial skeletal muscle biopsies obtained from the study of targeted risk reduction intervention through defined exercise (STRRIDE). STRRIDE participants were overweight and exhibited symptoms characteristic of the metabolic syndrome that typically precedes type II diabetes such as insulin resistance, abnormal lipids and glucose intolerance. Expression data were statistically filtered and sorted into exercise training-responsive clusters based on gene product knowledge. One such cluster included genes that promote the degradation of fibrin clots such as tissue plasminogen activator (t-PA), connective tissue activation peptide III (CTAP III) and tetranectin. The fibrinolytic activity and protein levels of tetranectin, and t-PA and its endogenous inhibitor PAI-1, were subsequently shown to change significantly in both skeletal muscle and serum in response to exercise training. Our data show that the rigors of exercise directly induce fibrinolytic genes and protein cascades, both within muscle, and in the systemic circulation. This finding is particularly significant given that the metabolic syndrome is an independent risk factor for peripheral vascular disease and thrombotic events within the heart and brain. We conclude that aerobic exercise training induces both local and systemic changes in fibrinolysis and vascular homeostasis that are probably protective against cardiovascular disease.
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PMID:Skeletal muscle dictates the fibrinolytic state after exercise training in overweight men with characteristics of metabolic syndrome. 1261 18

Elevated levels of haemostatic factors including tissue plasminogen activator (t-PA) antigen are associated with coronary heart disease in Europeans but data in South Asians are sparse. We performed a cross-sectional study of 111 healthy men and women aged 40-55 years (56 European and 55 Asian) frequency matched across a wide range of body mass index (17-34 kg/m2). All subjects had detailed adiposity and metabolic measurements, and five haemostatic factors were determined. South Asians had greater insulin resistance than Europeans (fasting insulin geometric mean, 7.1 versus 4.7 microU/ml, and 2-h insulin, 37.3 versus 14.1 microU/ml, respectively). There were no significant ethnic differences in the mean concentrations of fibrinogen, factor VII, von Willebrand factor, or fibrin D-dimer (P > 0.10). However, the t-PA antigen concentration was significantly elevated in South Asians compared with Europeans (mean, 10.6 versus 8.2 ng/ml, P = 0.001). t-PA correlated positively in both ethnic groups with features of the metabolic syndrome but the ethnic difference in t-PA persisted after adjustment for adiposity, metabolic and inflammatory variables (beta = 2.0, 95% confidence interval = 0.5-3.6, P = 0.012). We therefore hypothesize that elevated t-PA antigen may be a novel mechanism contributing to increased cardiovascular risk in South Asians.
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PMID:Specific elevation in plasma tissue plasminogen activator antigen concentrations in South Asians relative to Europeans. 1461 56

Testicular cancer patients have an increased risk for coronary artery disease more than ten years after cisplatin-based chemotherapy. We investigated whether vascular changes, including endothelial dysfunction, are present earlier. Ninety chemotherapy-treated testicular cancer patients (median follow-up of seven years) were compared with 44 patients after orchidectomy only and 47 healthy men. Microalbuminuria was present in 10 (12%) chemotherapy patients, one stage I patient and none of the controls. Chemotherapy patients had higher levels of fibrinogen, C-reactive protein (hs-CRP), von Willebrand factor (vWF), plasminogen activator inhibitor (PAI-1), and tissue-type plasminogen activator (t-PA). Chemotherapy patients with elevated PAI-1 (25/90) showed clustering of cardiovascular risk factors resembling the metabolic syndrome. In conclusion, cured testicular cancer patients showed a high prevalence of microalbuminuria and increased plasma levels of endothelial and inflammatory marker proteins, which might progress to more severe endothelial dysfunction and overt atherosclerosis.
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PMID:Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. 1501 71

Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-alpha and transforming growth factor-beta, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT(1)-receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease..
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PMID:Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. 1535 68

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA(1c) [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (<or=3 years), drug-naive, type 2 diabetic subjects (fasting plasma glucose <or=10 mmol/l), we examined a representative subgroup (n = 921) of the U.S. cohort in ADOPT (A Diabetes Outcome Progression Trial). The relationship between levels of CRP, fibrinogen, PAI-1 antigen and PAI-1 activity, and baseline variables including National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome phenotype were explored. All four factors increased significantly with increasing numbers of metabolic syndrome components (P = 0.0136 to P < 0.0001). BMI (P < 0.0001) and HOMA-IR (P < 0.0001) but not A1C (P = 0.65) increased with increasing numbers of metabolic syndrome components. Adjustment of CRP levels for BMI eliminated the association between CRP and the number of metabolic syndrome components, while adjusting for HOMA-IR did not (P = 0.0028). The relationships of PAI-1 antigen and PAI-1 activity with the number of metabolic syndrome components were maintained after adjusting for BMI (P = 0.0002 and P = <0.0001, respectively) or HOMA-IR (P = 0.0008 and P = <0.0001, respectively), whereas that with fibrinogen was eliminated after adjusting for BMI but not after adjusting for HOMA-IR (P = 0.013). Adjustment for A1C had no effect on any of the relationships between the inflammatory and fibrinolytic factors and the metabolic syndrome. We conclude that in recently diagnosed, drug-naive type 2 diabetic subjects, markers of inflammation and fibrinolysis are strongly related to the number of metabolic syndrome components. Further, for CRP and fibrinogen this relationship is determined by body adiposity and not by insulin sensitivity or glucose control.
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PMID:Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. 1687 1

It is known that overweight induces fibrinolysis impairment. Since this association has not been completely explored in patients with venous thromboembolism (VTE), we aimed to investigate its presence in young women with VTE and, if present, to determine its extent and the factors that influence it. Thirty women aged 23-49 years in the stable period after VTE were included [19 overweight (body mass index > or = 25) and 11 normal weight]; 52 healthy women (27 overweight and 25 normal weight) served as controls. The euglobulin clot lysis time (ECLT), plasminogen, D-dimer, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen and activity, lipids, fasting plasma glucose, insulin, fibrinogen, interleukin-6 and sedimentation rate were compared between the groups. Overweight patients had more impaired fibrinolysis (delayed ECLT, higher PAI-1 and t-PA antigen) than overweight controls (and normal weight patients). There was no difference in levels of insulin, glucose, fibrinogen and interleukin-6, whereas the sedimentation rate was significantly elevated in overweight patients compared with overweight controls [16 (8-31) versus 8 (5-12), P < 0.05]. The sedimentation rate in overweight patients significantly correlated with body mass index, ECLT, t-PA and PAI-1 antigen, but not with fibrinogen or interleukin-6. We found that overweight VTE patients have more prominent fibrinolysis impairment than predictable from parameters of metabolic syndrome and that is associated with an elevated sedimentation rate. This association could represent a new thrombotic risk profile in overweight women.
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PMID:A metabolic syndrome independent association between overweight, fibrinolysis impairment and low-grade inflammation in young women with venous thromboembolism. 1698 50

The metabolic syndrome (MetS) often accompanies obesity and contributes to the increased risk of atherothrombotic events with increased body fatness. Indeed, the risks for coronary artery disease and acute vascular events are greater with obesity combined with MetS compared with obesity alone. Endothelial release of tissue-type plasminogen activator (t-PA) is a key defense mechanism against thrombosis and has been shown to be impaired with obesity. The aim of the present study was to determine whether the presence of MetS exacerbates endothelial fibrinolytic dysfunction in obese adults. Net endothelial release of t-PA was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside in 47 sedentary adults: 15 normal weight (age 57 +/- 2 yr; body mass index 22.9 +/- 0.5 kg/m(2)), 14 obese but otherwise healthy (55 +/- 1 yr; 29.4 +/- 0.3 kg/m(2)), and 18 obese with MetS (55 +/- 2 yr; 32.3 +/- 1 kg/m(2)). MetS was established according to National Cholesterol Education Program ATP III criteria. Net release of t-PA antigen to bradykinin was approximately 50% lower (P < 0.01) in the obese (from 2.5 +/- 1.9 to 37.1 +/- 5.3 ng.100 ml tissue(-1).min(-1)) and obese with MetS (from 0.4 +/- 0.8 to 32.5 +/- 3.8 ng.100 ml tissue(-1).min(-1)) compared with normal-weight (from 0.9 +/- 1.0 to 74.3 +/- 8.1 ng.100 ml tissue(-1).min(-1)) subjects. However, there were no significant differences in the capacity of the endothelium to release t-PA in the obese and obese with MetS adults. These results indicate that the presence of the MetS does not worsen the obesity-related endothelial fibrinolytic dysfunction.
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PMID:Metabolic syndrome and endothelial fibrinolytic capacity in obese adults. 1795 3

Metabolic syndrome is considered a hyperinsulinemic and inflammatory state closely associated to endothelial dysfunction causing an increased incidence of ischemic cardiovascular events and high mortality. The main objective of the present study was to determine whether leukocitary and soluble cell adhesion molecules were altered in patients with metabolic syndrome in comparison with control subjects. Cell adhesion molecules, mainly of leukocitary location, have been not previously evaluated in specifically designed cross-sectional studies involving male patients with metabolic syndrome. Moreover, other circulating markers of different candidate atherogenic risk parameters were also studied and the potential existence of a progressive relation between the number of metabolic syndrome components and the above mentioned biomarkers was analyzed. Thirty one male patients with metabolic syndrome (ATPIII definition) and 56 male control subjects were studied. We evaluated different markers of insulin resistance, inflammation and atherosclerosis, as well as protective factors. Patients with metabolic syndrome showed (a) hypoadiponectinemia (4551 +/- 2302 ng/ml vs. 5865 +/- 2548 ng/ml, respectively; p<0.05), (b) an atherogenic lipid and lipoprotein profile, (c) altered HDL chemical composition accompanied by higher cholesteryl ester-triglyceride interchange carried out by CETP, (d) diminished Lp-PLA(2) activity (6.5 +/- 1.9 vs. 7.3 +/- 2.2, p<0.05, respectively), antioxidant enzyme related with LDL oxidation, which was positively associated with QUICKI and negatively with VCAM-1 and lymphocyte CD18, and (e) high soluble (VCAM-1: 17 +/-5 vs. 13 +/- 4 ng/ml, respectively; p<0.0005) and leukocyte adhesion molecule expression (monocyte CD54: 52 +/- 15 vs. 45 +/-12 arbitrary units, respectively; p<0.0005; and lymphocyte CD49d: 312 +/- 56 vs. 284 +/- 64 arbitrary units, respectively; p < 0.05). The increment in leukocyte and soluble cell adhesion molecules, crucial for leukocyte interaction with the endothelium and migration into the artery wall, in combination with the other disorders described above reinforce the presence of a clinical status with high propensity to type 2 diabetes and atherosclerotic cardiovascular disease.
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PMID:Alterations in cell adhesion molecules and other biomarkers of cardiovascular disease in patients with metabolic syndrome. 1809 67

The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is responsible for the degradation of fibrin into soluble degradation products. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). There are 3 types of PAIs described so far but the most important fibrinolytic inhibitor in vivo is PAI type 1 (PAI-1). Among others, the presence of metabolic syndrome and the -675 4G/5G promoter polymorphism are known to be modulators of PAI-1 levels. Besides their fibrinolytic profile, plasmin and plasminogen activators are implicated in tissue proliferation and cellular adhesion, as they can proteolytically degrade the extracellular matrix and regulate the activation of both growth factors and matrix metalloproteinases. By all these means, the fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis and cancer. PAI 1 has been studied in different settings with thrombotic pathophysiology, such as coronary artery disease and ischaemic stroke. Controversial results have been published and concerns about study designs or presence of confounders have been claimed to be responsible of them. Recently, its involvement in adverse thrombotic events related to the modern drug-eluting coronary stents has renewed the interest of its study. PAI-1 also plays an important role in signal transduction, cell adherence, and migration. Indeed, studies of several types of cancers, including breast cancer, have shown that increased uPA and PAI-1 levels are associated with aggressive tumor behavior and poor prognosis. Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus with marked ability to attach and invade the peritoneum. It is one of the most frequent benign gynecological diseases that affect women with pelvic pain or infertility during their reproductive age. Immune system disorders, genetic predisposition, altered peritoneal environment and endometrial alterations are believed to increase the susceptibility to endometriosis. The plasminogen activator system may be involved in this process, where local extracellular proteolysis plays a crucial role. Altered expression of several components of the fibrinolytic system in both eutopic and ectopic endometrium and peritoneal fluid of women with the disease has been implicated not only in the onset, but also in the progression of the endometriotic lesions.
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PMID:Fibrinolysis: the key to new pathogenetic mechanisms. 1847


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