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)

The 'metabolic syndrome' is a special clinical entity characterized by upper body segment obesity (android obesity), together with one or more of a constellation of metabolic disorders that includes glucose intolerance, which may amount to frank diabetes mellitus, hypertension, cardiovascular lesions, hyperuricemia, and dyslipidemias (hypercholesterolemia, hypertriglyceridemia and reduced serum HDL). Recently, lipoprotein (Lp) (a) proved to be a new member in this syndrome. Lp(a) has the distinctive feature of containing apolipoprotein (a), which is a glycoprotein linked to apo B100, and has a similarity to plasminogen; it is also structurally related to LDL. Lp(a) is a macromolecular complex which is genetically determined, and has been identified as an independent risk factor for premature coronary artery disease (CAD). It is elevated in diabetic and non-diabetic android obese subjects, and aggravates the atherogenic effect of diabetes mellitus. Lp(a) is poorly influenced either by dietary measures or by hypolipidemic drugs. Unfortunately, few pharmacologic agents, such as niacin, nicotinic acid, sex hormones (estrogen and testosterone), alcohol and neomycin, affect Lp(a).
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PMID:Lipoprotein (a) in android obesity and NIDDM: a new member in 'the metabolic syndrome'. 1066 39

The increased risk of coronary heart disease associated with the metabolic syndrome may be partially explained by prothrombotic deviations of the haemostatic system. Individuals with insulin resistance, dyslipidaemia and obesity are characterized by elevated plasma fibrinogen and factor VII coagulant activity levels and raised concentrations of plasminogen-activator inhibitor, the main inhibitor of endogenous fibrinolysis. These haemostatic abnormalities may be corrected with dietary treatment of the underlying clinical disorder. Dietary trials of diseased and healthy volunteers suggest that the optimal antithrombotic diet is a low-fat diet with a high content of foods rich in complex carbohydrates and dietary fibre. The dietary fatty acid composition has a profound effect on blood lipids, but seems of minor importance for the haemostatic system.
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PMID:Dietary treatment of thrombogenic disorders related to the metabolic syndrome. 1088 2

Abdominal obesity has been linked to the development of insulin resistance and Type 2 diabetes mellitus (DM2). By surgical removal of visceral fat (VF) in a variety of rodent models, we prevented insulin resistance and glucose intolerance, establishing a cause-effect relationship between VF and the metabolic syndrome. To characterize the biological differences between visceral and peripheral fat depots, we obtained perirenal visceral (VF) and subcutaneous (SC) fat from 5 young rats. We extracted mRNA from the fat tissue and performed gene array hybridization using Affymetrix technology with a platform containing 9 000 genes. Out of the 1 660 genes that were expressed in fat tissue, 297 (17.9 %) genes show a two-fold or higher difference in their expression between the two tissues. We present the 20 genes whose expression is higher in VF fat (by 3 - 7 fold) and the 20 genes whose expression is higher in SC fat (by 3 - 150 fold), many of which are predominantly involved in glucose homeostasis, insulin action, and lipid metabolism. We confirmed the findings of gene array expression and quantified the changes in expression in VF of genes involved in insulin resistance (PPARgamma leptin) and its syndrome (angiotensinogen and plasminogen activating inhibitor-1, PAI-1) by real-time PCR (qRT-PCR) technology. Finally, we demonstrated increased expression of resistin in VF by around 12-fold and adiponectin by around 4-fold, peptides that were not part of the gene expression platform. These results indicate that visceral fat and subcutaneous fat are biologically distinct.
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PMID:Differential gene expression between visceral and subcutaneous fat depots. 1266 Aug 71

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of urokinase-type and tissue-type plasminogen activators. It has gained special interest among clinicians because a number of pathological conditions, such as myocardial infarction, atherosclerosis, thrombosis, several types of cancer, and the metabolic syndrome, as well as type 2 diabetes mellitus, are associated with increased PAI-1 levels. Interestingly, a number of these diseases are also accompanied by oxidative stress and the enhanced production of reactive oxygen species or tissue hypoxia. This article tries to summarize some aspects leading to enhanced PAI-1 production under oxidative stress or hypoxia.
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PMID:Oxidative stress and hypoxia: implications for plasminogen activator inhibitor-1 expression. 1524 48

Plasminogen activator inhibitor-1 (PAI-1), is a serpin whose major function is to negate plasminogen activation and impair fibrinolysis. It occurs in plasma and tissues. Studies in genetically modified mice indicate that PAI-1 might be involved in thrombosis, vascular healing and atherosclerosis although contradictory findings have been obtained in the latter two processes. Differences between results depend on the types and the lengths of the models and underline the fact that besides its role in regulating fibrinolysis, PAI-1 plays a role in several cellular processes independent of plasminogen activation. In patients, high plasma PAI-1 levels worsen the prognosis of myocardial infarction in the acute phase and have been considered as a risk factor for coronary heart disease. The predictive capacity of PAI-1 is mainly related to several metabolic covariates which constitute the metabolic syndrome (MS). This syndrome is associated with increased cardiovascular morbidity and mortality and is becoming one of the major health problems as its prevalence is growing rapidly. Accelerated atherothrombotic process in the MS is attributed not only to metabolic abnormalities but also to a specific inflammatory state which leads to increased plasma PAI-1 levels. Modifying PAI-1 expression by PAI-1 inhibitors may open a new field of research and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes.
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PMID:Contribution of PAI-1 in cardiovascular pathology. 1528 42

Increased visceral adiposity is a pivotal component of the metabolic syndrome. Differential gene expression patterns of fat-derived peptides (FDPs) in visceral fat and subcutaneous fat have been characterized in the fasting state. Here we examined whether delivery of nutrients differentially affects the expression of FDPs in visceral fat versus subcutaneous fat (in the fed state). We increased the rate of glucose flux into adipose tissue of normal rats (n = 16) by hyperglycemia or hyperinsulinemia using the clamp technique. Glucose uptake was associated with increased expression of FDPs, including resistin ( approximately 5-fold), adiponectin ( approximately 2-fold), leptin ( approximately 15-fold), plasminogen activating inhibitor-1 ( approximately 10-fold), and angiotensinogen ( approximately 4-fold) in visceral fat, but markedly less in subcutaneous fat. Cytokine expression derived mainly from vascular/stromal/macrophage components of adipose tissue was less dramatically increased. Infusion of glucosamine amplified the results obtained by increasing glucose uptake into adipose tissue, suggesting that flux through the hexosamine biosynthetic pathway may serve as a mechanism for "nutrient sensing." Nutrient-dependent expression of FDPs in visceral fat was also associated with increased plasma levels of several FDPs. Because a biologic sensing pathway can dynamically couple daily food intake to abnormal plasma levels of important FDPs, we challenge the practice of obtaining plasma levels after fasting to assess risk factors for metabolic syndrome.
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PMID:Differential responses of visceral and subcutaneous fat depots to nutrients. 1573 42

There is a considerable body of evidence supporting an association between hypertriglyceridaemia, a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade. Fibrinolysis is also less efficient when thrombin is generated. Thrombin induces thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor is a carboxypeptidase that cleaves the carboxylic lysine residues on fibrin, thereby abolishing the critical binding site for tPA-plasminogen decreasing plasmin formation. Thus the evidence is supportive of dysregulated coagulation, and impaired fibrinolysis with a predisposition to atherothrombosis, in conditions such as the metabolic syndrome, in which there are increased concentrations of VLDL and remnant lipoproteins. The purpose of this review is to describe the current evidence supporting a procoagulant state induced by VLDL and remnant lipoproteins. The role of these lipoprotein classes in (1) platelet activation; (2) the intrinsic coagulation cascade, and (3) clot formation and fibrinolysis is discussed.
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PMID:Effects of VLDL and remnant particles on platelets. 1687 77

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

Thrombotic complications of vascular disease constitute the leading cause of morbidity and mortality in much of the developed world. Current drug therapies available to treat the thrombotic component of arterial and venous vascular complications remain limited. Novel safe and effective treatment strategies to reduce formation of occlusive thrombosis will likely have a major impact on reducing the economic burden of vascular disease on the healthcare system. Enhancing endogenous fibrinolysis by targeting plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of circulating plasminogen activators, has been shown to be effective in markedly attenuating the formation of arterial and venous occlusive thrombosis in animal models. In addition, animal and human studies of PAI-1 deficiency indicate that spontaneous bleeding complications associated with even complete PAI-1 deficiency would be rare. Patients most likely to benefit from PAI-1 inhibition would be those at high risk for vascular events where PAI-1 is elevated, such as is observed in obesity, diabetes and the metabolic syndrome. Since obesity and metabolic syndrome are now epidemic, and will likely have a major adverse impact on vascular thrombotic events, it may be time to test the clinical effectiveness of PAI-1 inhibition in a patient population at high risk for vascular thrombosis.
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PMID:Plasminogen activator inhibitor-1 in vascular thrombosis. 1789 48

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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