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

The effects of antihypertensive drugs on cardiovascular metabolic risk factors were monitored in 42 patients with essential hypertension (diastolic blood pressure [DBP] >95 mm Hg). In a double-blind randomized parallel-group study, they were treated with atenolol 50 mg once per day (n = 25) or urapidil 60 mg twice per day (n = 17), a peripheral alpha1-receptor blocker with an additional central serotonin 1A (5HT1A) receptor agonistic effect, for 12 weeks. Plasma fibrinogen concentration decreased by 24% (P < .0001) during urapidil treatment and by 9% (P = .05) during atenolol treatment, with the effects of the two drugs differing significantly. Plasminogen activator inhibitor (PAI) activity tended to increase by 17% (nonsignificant [NS]) in the atenolol-treated group and to decrease by 4% (NS) in the urapidil group. Differences between the effects of the two drugs on very-low-density lipoprotein (VLDL) triglycerides (TG) and on total TG were significant. During urapidil medication, these two parameters were reduced by 22% and 13%, respectively, but the changes were nonsignificant (P = .11 and P = .14, respectively). In contrast, atenolol treatment caused a significant increase in both VLDL TG and total TG of 31% and 21%, respectively. Hemoglobin A1c (HbA1c) increased by 4% (P = .06) during atenolol treatment, but was unaffected by urapidil. There were no significant changes within or between atenolol- and urapidil-treated groups regarding glucose disposal on an oral glucose tolerance test (OGTT) or the insulin sensitivity index on a hyperinsulinemic-euglycemic clamp test. In conclusion, urapidil treatment was characterized by neutral or favorable effects on several variables associated with the metabolic syndrome. Atenolol treatment had neutral properties in some metabolic aspects, but deleterious effects on lipid status.
 ...
PMID:Urapidil treatment decreases plasma fibrinogen concentration in essential hypertension. 884 76

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.
 ...
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.
 ...
PMID:Contribution of PAI-1 in cardiovascular pathology. 1528 42

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..
 ...
PMID:Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. 1535 68

Plasminogen activator inhibitor-1 (PAI-1) is produced by adipose tissue, and elevated PAI-1 levels in plasma are a risk factor in the metabolic syndrome. We investigated the regulatory effects of TNF-alpha and IL-6 on PAI-1 gene induction in human adipose tissue. Twenty healthy men underwent a 3-h infusion of either recombinant human TNF-alpha (n = 8), recombinant human IL-6 (n = 6), or vehicle (n = 6). Biopsies were obtained from the subcutaneous abdominal adipose tissue at preinfusion, at 1, 2, and 3 h during the infusion, and at 2 h after the infusion. The mRNA expression of PAI-1 in the adipose tissue was measured using real-time PCR. The plasma levels of TNF-alpha and IL-6 reached 18 and 99 pg/ml, respectively, during the infusions. During the TNF-alpha infusion, adipose PAI-1 mRNA expression increased 2.5-fold at 1 h, 6-fold at 2 h, 9-fold at 3 h, and declined to 2-fold 2 h after the infusion stopped but did not change during IL-6 infusion and vehicle. These data demonstrate that TNF-alpha rather than IL-6 stimulates an increase in PAI-1 mRNA in the subcutaneous adipose tissue, suggesting that TNF-alpha may be involved in the pathogenesis of related metabolic disorders.
 ...
PMID:TNF-alpha, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissue. 1567 34

In this multicentre, randomized, double-blind, controlled, parallel-group trial, 103 patients with type 2 diabetes mellitus and metabolic syndrome were randomized to receive one of two thiazolidinediones--pioglitazone or rosiglitazone--in combination with 1500 mg/day of metformin, increasing up to 3000 mg/day, for 12 months. Anthropometric, metabolic, coagulation and fibrinolysis parameters were assessed at baseline and after 3, 6, 9 and 12 months. Significant decreases in glycosylated haemoglobin, fasting plasma glucose and post-prandial plasma glucose levels were seen after 9 and 12 months in both groups, and significant decreases in fasting plasma insulin and post-prandial plasma insulin levels were seen after 12 months in both groups. In both groups, improvement in the homeostasis model assessment index compared with baseline was obtained only after 12 months. Plasminogen activator inhibitor-1 levels were significantly lower in both groups after 12 months compared with baseline values. In patients with type 2 diabetes mellitus and metabolic syndrome, the combination of metformin plus thiazolidinediones improved glycaemic control and produced a slight but significant reduction in plasminogen activator inhibitor-1 levels.
 ...
PMID:Effects of rosiglitazone and pioglitazone combined with metformin on the prothrombotic state of patients with type 2 diabetes mellitus and metabolic syndrome. 1713 85

Metabolic syndrome is defined as a complex of hypertriglyceride, insulin resistance, hypertension, and accumulation of visceral fat. This syndrome is often accompanied by thrombotic diseases (e.g., myocardial infarction, cerebral infarction), but the mechanism (s) of thrombotic tendency has not yet been elucidated. Plasminogen activator inhibitor-1 (PAI-1), a principal regulator of fibrinolytic system, plays a pathological role in the development of thrombosis and cardiovascular diseases. PAI-1 is regarded to be one of adipocytokines because it is produced and secreted by adipocytes. The expression of PAI-1 in adipocytes is upregulated by insulin, TNF-alpha, and TGF-beta, suggesting that it is relevant to insulin resistance. PAI-1 antigen level in plasma is elevated in obese subjects and increases in parallel with their BMI and visceral fat. It was experimentally revealed that PAI-1 expression in adipose tissue was dramatically increased in genetically obese mice and abundant expression of PAI-1 was localized to adipocytes in vivo. PAI-1 deficient mice were resistant to high fat diet-induced body weight gain, adipose accumulation, and insulin resistance in association with lack of decreased expression of adiponectin. Taken together, PAI-1 may be a key molecule to develop obesity and insulin resistance as well as thrombotic diseases. It is possible to prevent thrombotic complications and cardiovascular diseases in obese patients by controlling PAI-1 expression and function. Each pathology included in metabolic syndrome could stimulate PAI-1 expression, and thus, PAI-1 would be a good marker of progression of metabolic syndrome itself and of risk for thrombotic cardiovascular diseases as well.
 ...
PMID:[Thrombotic tendency and laboratory medicine in metabolic syndrome]. 1805 Jun 73

Obesity is a complex, multifactorial chronic disease frequently associated with cardiovascular risks, hypertriglyceridemia, low high-density lipoprotein-cholesterol, high blood pressure, and the insulin resistance that appears to be central to the pathogenesis of Type II diabetes. Plasminogen activator inhibitor-1 expression induced in differentiating adipose tissue, but its role in adipogenesis and obesity is poorly understood. Circulating plasminogen activator inhibitor-1 levels are elevated at an early stage of impaired glucose tolerance, resulting in diabetes and metabolic syndrome. Plasminogen activator inhibitor-1 levels are also significantly elevated in the plasma of obese individuals and in adipose tissues of obese mice and humans. Some investigators proposed that the -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter caused overexpression of this gene and predisposed carriers to obesity. In this study, we investigated the role of -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter in the expression of this gene and the contribution of plasminogen activator inhibitor-1 to adipogenesis. Using a dual-luciferase promoter assay, we determined that the -675 4G/5G polymorphism contributes significantly to overexpression of plasminogen activator inhibitor-1 in the course of adipogenesis. The antidiabetic agents troglitazone and ciglitazone inhibited reporter gene expression driven by wild-type and -675 4G/5G mutant promoter, as well as the expression of endogenous plasminogen activator inhibitor-1, indicating that suppression of plasminogen activator inhibitor-1 expression may contribute to antidiabetic effects of these agents. The results indicate that absence of plasminogen activator inhibitor-1 in adipocytes may protect the cells against insulin resistance by promoting glucose uptake and adipocyte differentiation via a decrease in the peroxisome proliferator activated receptor-gamma expression that modulates the adipocyte differentiation.
 ...
PMID:The effect of plasminogen activator inhibitor-1 -675 4G/5G polymorphism on PAI-1 gene expression and adipocyte differentiation. 1816 May 87

Polycystic ovary syndrome (PCOS) is a heterogeneous condition with unknown etiology and is considered to be the most common endocrine disorder in women of reproductive age. Two meta-analyses are presented here concerning the association of Plasminogen Activator Inhibitor 1 (PAI-1) 4G/5G polymorphism and the methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism with the risk of developing PCOS. Seven studies were included concerning PAI-1 (1538 cases, 710 controls) and six studies concerning MTHFR C677T (223 cases, 392 controls). Overall, a significant association was found for PAI-1, with the odds ratio (OR) for 4G carriers versus 5G homozygotes being equal to 1.600 (95% CI 1.052, 2.434) with strong evidence for dominant inheritance. There was however a large between-studies variability (I(2) = 67.3%). No evidence was found for association of MTHFR C677T polymorphism with PCOS (OR for the TT+CT versus CC comparison equal to 0.940 with 95% CI 0.561, 1.575). No evidence of publication bias was found in these meta-analyses. PAI-1 4G/5G polymorphism seems to be associated with the risk of developing PCOS. Further studies are needed in order to investigate the etiologic mechanism behind this association, as well as the interrelations with other components of the metabolic syndrome (hypertension, diabetes, etc.).
 ...
PMID:Plasminogen activator inhibitor-1 4G/5G and 5,10-methylene-tetrahydrofolate reductase C677T polymorphisms in polycystic ovary syndrome. 2270 71

Plasminogen activator inhibitor-1 (PAI-1) is secreted from adipose tissue and is considered to be a risk factor for both atherosclerosis and insulin resistance. Here we report for the first time that PAI-1 expression is enhanced by oxidized low-density lipoprotein (OxLDL) and its lipid component lysophosphatidylcholine (LPC) in mouse 3T3-L1 adipocytes. In fully differentiated 3T3-L1 cells, OxLDL treatment increased the mRNA expression and protein secretion of PAI-1 in a dose- and time-dependent manner, whereas native LDL had no effect. The addition of an anti-CD36 antibody suppressed OxLDL-stimulated PAI-1 expression by 50%, suggesting that adipose-derived CD36 contributes to roughly half of the PAI-1 expression stimulated by OxLDL. In addition, pharmacological experiments showed that the OxLDL-stimulated enhancement in PAI-1 expression was mediated through the generation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinase 1/2. Furthermore, LPC, a major lipid component of OxLDL, was responsible for the enhanced expression of PAI-1 as phospholipase A(2)-treated acetyl LDL, which generates LPC, strongly stimulated PAI-1 expression, whereas acetyl LDL itself had no such activity. These data demonstrate that the uptake of OxLDL and, in particular, its lipid component LPC into adipocytes triggers aberrant ROS-mediated PAI-1 expression, which may be involved in the pathogenesis of metabolic syndrome.
 ...
PMID:Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes. 2114 30


1 2 Next >>