Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 29-year old man was admitted to an emergency psychiatric ward because of exacerbation of a chronic paranoid schizophrenia. He was restrained after arrival, and seven days later a deep venous thrombosis and a pulmonary embolism were diagnosed. No haematological predisposing factors (coagulation inhibitor deficiency, activated protein C resistance, or antiphospholipid antibodies) were identified, except for a questionable borderline increase of the fibrinolysis inhibitor PAI-1, and combined type II hyperlipidaemia. During the last 15-20 years, there has been a considerable reduction in the use of restraint and seclusion in Norway. The use of seclusion and restraint may be effective in preventing injury and reducing agitation, but these procedures may also have harmful physical, and in particular psychological side-effects. To our knowledge, this is the first report to demonstrate an association between venous thromboembolism and physical restraint. Immobilisation is a well-known risk factor for thrombophlebitis, and special attention should be paid to this problem on psychiatric wards. However, until more is known about thrombosis in relation to restraint, it is not advisable to recommend prophylactic treatment of thrombosis.
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PMID:[Venous thromboembolism in connection with physical restraint]. 965 10

The aim of this study was to compare fibrinolytic parameters in two subgroups of young survivors of myocardial infarction: group A (n = 14) with silent myocardial ischaemia and group B (n = 15) without silent myocardial ischaemia, as assessed by 24 h Holter electrocardiogram monitoring. Only men aged 33-46 years who were in a stable condition at least 6 months after the acute event were included in the survey. All patients were normolipaemic or had only mild hyperlipidaemia, non-diabetic, normotensive, non-current smokers and with a normal body mass index. The control group consisted of 15 age-matched healthy men. Blood samples were taken at 7.30 a.m. In the group A patients, we found higher mean levels of tissue plasminogen activator (t-PA) total antigen (11.1 versus 6.9 ng/ml, P < 0.01), its inhibitor plasminogen activator inhibitor-1 (PAI-1) antigen (58.1 versus 34.8 ng/ml, P < 0.01), PAI-1 activity (4.9 versus 3.4 U/ml, P < 0.05) and tPA-PAI-1 complexes (5.1 versus 3.5 ng/ml, P < 0.05) as well as a lower level of t-PA activity (0.5 versus 0.8 IU/ml, P < 0.01) and free t-PA antigen (0.8 versus 1.3 ng/ml, P < 0.01) compared with the controls. However, group A patients exhibited higher PAI-1 antigen levels (58.1 versus 41.6 ng/ml, P < 0.05) than those without silent ischaemia. There were no differences between group B and controls in any of the parameters measured. Our results indicate that patients with more severe disease, as revealed by silent myocardial ischaemia, had lower levels of free t-PA as a result of the excess of PAI-1.
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PMID:Impairment of plasma fibrinolysis in young survivors of myocardial infarction with silent ischaemia. 966 7

Elevated plasminogen activator inhibitor-1 (PAI-1) levels have been described in some populations to associate with hyperinsulinaemia in the metabolic syndrome which predisposes to coronary heart disease (CHD). This association, if consistently present, could provide more evidence for a synergistic role for insulin resistance and altered fibrinolysis in the pathogenesis of CHD. To test the hypothesis further therefore, we explored the relationships between the fasting levels of insulin and PAI-1 and lipids in groups of non-diabetic Arab subjects classified as: A: normolipidaemic (n = 148); B: hyperlipidaemic: (n = 99), subdivided into - C: normotensive (n = 71) and D: hypertensive (n = 28); and E: patients with CHD (n = 12). In Group A, fasting insulin (FI) was 7.2+/-(SD) 3.4 mU/l, PAI-1 30.6+/-9.7 ng/ml, both levels significantly lower (P < 0.05) than in Group B as a whole (FI 9.7+/-5.2, PAI-1 36.9+/-10.6), or as normotensive Group C (FI 9.4+/-5.4, PAI-1 36.7+/-10.3) or hypertensive Group D (FI 10.9+/-4.8, PAI-1 37.2+/-11.5). These values were highest in the hyperlipidaemic hypertensive Group D. There were no significant differences relative to the hyperlipidaemic phenotype of predominant hypercholesterolaemia, hypertriglyceridaemia or mixed hyperlipidaemia. PAI-1 (34.7+/-13.8) and FI (7.0+/-2.4) levels in Group E with CHD were similar to those of Group A but lower than values seen in Groups B, C and D. Consistent positive correlations (r = 0.32-0.41, P <0.01) were demonstrable in all the groups between PAI-1 and triglycerides levels. There were also significant correlations between insulin and PAI-1 (r = 0.20, P<0.1) in all the subjects (grouped as a whole, n = 259) and in normolipidaemic Group A (r = 0.29, P < 0.01) but not in any of the hyperlipidaemic groups or in patients with CHD. This study therefore suggests that levels of insulin and PAI-1 are increased in hyperlipidaemic subjects, particularly when also hypertensive. The further observation of significant correlations between insulin and PAI-1 levels only in normolipidaemic subjects and not those who were hyperlipidaemic or with CHD is at variance with observations in Caucasians in whom strong positive correlations between insulin and PAI-1 had suggested that elevated PAI-1 levels should constitute one more component of the metabolic syndrome which strongly predisposes to CHD. Whether this is a racial variation or an artifact of the insulin/PAI-1 assay methodology is unclear and deserves further study.
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PMID:The relationships between insulin and plasminogen activator inhibitor 1 levels: assessment in groups of subjects with dyslipidaemia and hypertension. 968 96

Whether the post-prandial lipemic response is linked to potentially pro-atherogenic and/or prothrombotic changes in plasminogen activator inhibitor (PAI) and transforming growth factor-beta (TGF-beta) is uncertain. The aim of our study was to determine whether PAI-1 antigen and PAI activity were elevated during post-prandial lipemia following a standard fat tolerance test. We also investigated changes in TGF-beta1 antigen and TGF-beta activity, to determine whether changes in TGF-beta activity were associated with changes in PAI measurements. Lastly, the influence of genotype at a common insertion/deletion polymorphism in the PAI-1 promoter on changes in PAI activity and PAI-1 antigen was examined. Fat tolerance tests were undertaken in 57 healthy middle-aged men to investigate associations between plasma concentrations of lipoproteins, PAI (antigen and activity) and TGF-beta. PAI-1 concentration increased by 76% after 8 h (P < 0.0001). PAI activity also increased by 64% (P = 0.0054) and TGF-beta activity decreased by 10% (P < 0.0001). Increases in PAI-I antigen and PAI activity varied markedly between individuals. To investigate these heterogeneous responses we examined whether genotype at the common insertion/deletion polymorphism of the PAI-1 promoter accounted for these differences. Individuals with at least one 4G (deletion) allele showed potentially pro-atherogenic changes in both PAI-1 and TGF-beta, compared to individuals who were homozygous for the 5G (insertion) allele. In conclusion, increased PAI and decreased TGF-beta activity occur during a fat tolerance test and this effect may be modulated by a common insertion/deletion polymorphism in the PAI-1 promoter.
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PMID:Increased PAI activity and PAI-1 antigen occurring with an oral fat load: associations with PAI-1 genotype and plasma active TGF-beta levels. 973 14

Fibrinolysis is essential for maintaining the fluency of blood flow. Attenuated fibrinolytic activity has been frequently detected in coronary artery disease, peripheral vascular diseases, diabetes, hyperlipidaemia and obesity. The biologically active product of fibrinolytic system is plasmin. Generation of plasmin is regulated by plasminogen activators (PA) and their inhibitors (PAI). Vascular endothelial and smooth muscle cells synthesize tissue-type and urokinase-type PA (tPA and uPA) and their major physiological inhibitor, PAI-1. The production of fibrinolytic regulators is modulated by a number of biological factors related to thrombosis and atherosclerosis, including coagulation factors, hormones, growth factors, inflammatory mediators and lipoproteins. Several anticoagulants, including heparin, hirudin and hirulog-1, affect the production of fibrinolytic regulators in vascular cells. Studies in knockout mice demonstrated that mice deficient in PA or plasminogen are susceptible to thrombosis during inflammation or injury. Overexpression of uPA or deficiency of PAI-1 promotes neointima and aneurysm formation, which is probably due to active remodelling of extracellular matrix in vascular wall caused by excess plasmin. Long-term effect of treatment with thrombolytic agents or in atheroscleronic cardiovascular diseases remains to be defined. Future studies on determination of the role of PA and PAI in vascular remodelling may help understand the mechanism for neointima formation and orient the prevention of restenosis following vascular procedures.
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PMID:Vascular cell-derived fibrinolytic regulators and atherothrombotic vascular disorders (Review). 985 42

Fibrates are hypolipaemic agents with a broad spectrum of action and long-term safety. They reduce the cardiovascular mortality and morbidity and can induce also regression of coronary atherosclerosis. They lower the plasma concentration of total and LDL-cholesterol, triacylglycerols, and produce a rise of HDL-cholesterol. Moreover they can reduce the level of fibrinogen, lipoprotein/a/, PAI-1, uric acid and the concentration of highly atherogenic small dense LDL3. Their effect is mediated by activation of "peroxisome proliferator-activated receptors" (PPARs) in the cell nucleus. At present we find on the market second generation fibrates as well as modern micronized medicaments of the third generation. They are indicated for treatment of patients with hypertriglyceridaemia, combined hyperlipidaemia and diabetic dyslipidemia.
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PMID:[Present status of fibrates in the treatment of hyperlipoproteinemias]. 1104 65

High plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of cardiovascular disease. There is also a close relation between high plasma levels of PAI-1 and hypertriglyceridemia. Cell culture studies have shown that very low density lipoprotein (VLDL) increases the production and secretion of PAI-1 in endothelial cells and hepatocytes, suggesting a possible mechanism for this association. To determine whether VLDL stimulates PAI-1 production in vascular cells also in vivo, Sprague-Dawley rats were injected intravenously with 6 mg/kg of VLDL (derived from human subjects with type IV hyperlipidemia). Previous studies have demonstrated that this results in an accumulation of human VLDL in the aorta and other arteries followed by increased nuclear factor-kappa B (NF-kappaB) activation. Endothelial, but not smooth muscle cells, showed a basal PAI-1 mRNA and protein expression as assessed by in situ hybridization and immunohistochemistry, respectively. Six to twenty-four hours after the VLDL injection, lipoprotein particle accumulation was seen in the aortic wall, which was accompanied by increasing PAI-1 mRNA and protein expression in endothelial and smooth muscle cells. Within the rat PAI-1 promoter we identified a sequence located at -589 to -571 with 74% homology with the recently described VLDL responsive element in the human PAI-1 promoter and located adjacent to a 4-guanosine motif presumably corresponding to the human 4G/5G polymorphism. Transient transfection studies showed that VLDL exerts its stimulatory effects on rat PAI-1 gene expression in vascular cells by interaction with promoter sequences located within bp -656 and -505. Electrophoretic mobility shift assays showed that VLDL increases the binding of as yet incompletely characterized factors to this response element. Taken together these observations support a direct influence of VLDL on vascular PAI-1 gene expression ill vivo. This stimulation is exerted on the level of PAI-1 gene transcription, and involves transcription factor binding to a VLDL responsive element adjacent to a 4G motif within the PAI-1 promoter.
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PMID:In vivo stimulation of vascular plasminogen activator inhibitor-1 production by very low-density lipoprotein involves transcription factor binding to a VLDL-responsive element. 1105 74

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFalpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFalpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.
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PMID:Molecular mechanisms of insulin resistance and the role of the adipocyte. 1112 35

Cardiovascular disease (CVD) risk associated with fat redistribution seen among HIV-infected individuals remains unknown, but may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prothrombotic state associated with these metabolic abnormalities. In this study we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) antigen levels, markers of fibrinolysis and increased CVD risk, in HIV lipodystrophic patients compared to controls. Furthermore, we investigated the effect of treatment with metformin on PAI-1 and tPA antigen levels in patients with HIV-associated fat redistribution. Eighty-six patients (age 43 +/- 1 yr, BMI 26.1 +/- 0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin >15 microU/mL [104 pmol/L] or impaired glucose tolerance, but without diabetes mellitus were enrolled in a placebo-controlled treatment study of metformin 500 mg twice daily. PAI-1 and tPA antigen levels were significantly increased in patients with HIV related fat redistribution compared to Framingham control subjects (46.1 +/- 4 vs 18.9 +/- 0.9 microg/L PAI-1, 16.6 +/- 0.8 vs. 8.0 +/- 0.3 microg/L tPA, P = 0.0001). Among patients with HIV infection, a multivariate regression analysis including age, sex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and insulin area under the curve (AUC), found gender and insulin AUC were significant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9 +/- 1.4 vs +1.4 +/- 1.0 microg/L in the placebo-treated group P = 0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7 +/- 2.3 vs +1.7 +/- 2.9 microg/L, P = 0.03). Change in insulin AUC correlated significantly with change in tPA antigen (r = 0.43, P = 0.03). PAI-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD risk, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrations in these patients and may ultimately improve associated CVD risk.
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PMID:Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. 1115 71

Diabetes mellitus, hyperlipidemia, hypertension and atherosclerotic diseases have recently defined as typical life style-related diseases. A common background of these life style-related diseases is overnutrition and its consequence, obesity. Recent advances in the biology of adipose tissue have revealed that adipose is not simply an energy storage organ but it also secretes a variety of molecules which affect the metabolism of the whole body. Through a systematic search of active genes in adipose tissue, we found that adipose tissue, especially visceral fat expressed numerous genes for secretory proteins. Among them, plasminogen activator inhibitor-1(PAI-1) was over expressed in the visceral fat in an animal model of obesity. Plasma level of PAI-1 was closely correlated with visceral adiposity in human. Thus, PAI-1 secreted from visceral fat may play an important role in vascular disease in visceral obesity. Adiponectin, a novel adipose-specific gene product, is abundantly presented in human plasma. This molecule has been shown to have protective roles against atherosclerotic vascular changes and its plasma level is negatively correlated with visceral adiposity. In conclusion, dysregulated secretion of these adipose-specific secretory proteins(adipocytokines) may have important roles in the development of life style-related diseases, especially atherosclerotic diseases.
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PMID:[Life style-related disease]. 1119 54


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