Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

-Migration of vascular smooth muscle cells (VSMC) is a key event in neointimal formation and atherosclerosis that may be linked to the accumulation of inflammatory cells and release of chemotactic cytokines. Tumor necrosis factor-alpha (TNF-alpha) induces chemotaxis of inflammatory cells and fibroblasts, but little is known about chemotactic signaling by TNF-alpha in VSMC. The aim of this study was to investigate the role of TNF-alpha in VSMC migration and to elucidate the chemotactic signaling pathways mediating this action. TNF-alpha (50 to 400 U/mL) induced migration of cultured rat aortic VSMC in a dose-dependent manner. Because activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) is known to be required in platelet-derived growth factor-directed and angiotensin II-directed migration of these cells, we used the MAPK-inhibitor PD98059 to determine if chemotactic signaling by TNF-alpha involves the MAPK pathway as well. We found that TNF-alpha-directed migration was substantially inhibited by PD98059. TNF-alpha (100 U/mL) transiently activated MAPK with a maximal induction 10 minutes after stimulation that returned to baseline levels by 2 hours after treatment. Only a single peak of increased MAPK activity was seen. PD98059 also blocked TNF-alpha-stimulated MAPK activation in a concentration-dependent manner, which is consistent with its inhibition of TNF-alpha-directed migration. To identify which TNF-alpha receptor is involved in TNF-alpha-induced MAPK activation, antibodies against the p55 TNF-alpha receptor-1 (TNF-R1) and the p75 TNF-alpha receptor-2 (TNF-R2) were used. VSMC express both receptors, but TNF-alpha-induced MAPK activation was inhibited only by the TNF-R1 antibody. The TNF-R2 antibody had no effect. Thiazolidinediones are known to inhibit TNF-alpha signaling in adipose tissue and attenuate platelet-derived growth factor-directed and angiotensin II-directed migration in VSMC. We therefore investigated the effects of the thiazolidinediones troglitazone (TRO) and rosiglitazone (RSG) on TNF-alpha-induced migration. Both TRO and RSG inhibited migration, but neither attenuated TNF-alpha-induced MAPK activation, indicating that their antimigration activity was exerted downstream of MAPK. These experiments provide the first evidence that early activation of MAPK is a crucial event in TNF-alpha-mediated signal transduction leading to VSMC migration. Moreover, inhibition of TNF-alpha-directed migration by the insulin sensitizers TRO and RSG underscores their potential as vasculoprotective agents.
Hypertension 1999 Jan
PMID:TNF-alpha-induced migration of vascular smooth muscle cells is MAPK dependent. 993 Nov 2

Obesity is associated with a cluster of abnormalities, including hypertension, insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor beta (TGF-beta). Although these changes may increase the risk for accelerated atherosclerosis and fatal myocardial infarction, the underlying molecular mechanisms remain to be defined. Although tumor necrosis factor alpha (TNF-alpha) has been implicated in the insulin resistance associated with obesity, its role in other disorders of obesity is largely unknown. In this report, we show that in obese (ob/ob) mice, neutralization of TNF-alpha or deletion of both TNF receptors (TNFRs) results in significantly reduced levels of plasma PAI-1 antigen, plasma insulin, and adipose tissue PAI-1 and TGF-beta mRNAs. Studies in which exogenous TNF-alpha was infused into lean mice lacking individual TNFRs indicate that TNF-alpha signaling of PAI-1 in adipose tissue can be mediated by either the p55 or the p75 TNFR. However, TNF-alpha signaling of TGF-beta mRNA expression in adipose tissue is mediated exclusively via the p55 TNFR. Our results suggest that TNF-alpha is a common link between the insulin resistance and elevated PAI-1 and TGF-beta in obesity. The chronic elevation of TNF-alpha in obesity thus may directly promote the development of the complex cardiovascular risk profile associated with this condition.
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PMID:Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. 1035 11

Tumor necrosis factor (TNF) receptor 2 (TNF-R2) has been implicated in insulin resistance and metabolic syndrome disorders, one of which is hypertension (HT). We therefore decided to test markers in and near the TNF-R2 gene (TNFRSF1B) for linkage and association with HT, as well as hypercholesterolemia, and plasma levels of the shed soluble receptor (sTNF-R2). The linkage study, which involved 200 HT Anglo-Celtic Caucasian sibpairs, indicated a sharp, significant linkage peak centered at TNFRSF1B (multipoint maximum LOD score = 2. 6 and 3.1 by weighted and unweighted MAPMAKER/SIBS, respectively; two-point LOD scores = 2.9 and 3.9 by weighted and unweighted SPLINK, respectively; P = 10(-4) by identical-by-state chi(2)). The case-control study in 134 unrelated HTs who were the offspring of two HT parents and 197 normotensives (NTs) whose parents were both NTs, indicated possible association of TNFRSF1B with HT by haplotype analysis (P = 0.008). Plasma sTNF-R2 was elevated in HTs (P < 0. 0001) and showed a correlation with systolic and diastolic blood pressure (BP) (P < 0.0002). A genotypic effect of TNFRSF1B on plasma sTNF-R2, as well as total, low and high density lipoprotein cholesterol, and diastolic BP was observed. These observations are consistent with a scheme leading to raised BP and hypercholesterolemia. In conclusion, TNFRSF1B may be a candidate gene for HT and other metabolic syndrome abnormalities.
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PMID:Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor. 1094 22

Tumor necrosis factor (TNF)-alpha has been implicated in pathophysiological processes in coronary artery disease (CAD). TNF receptor 2 is of particular interest in mediating such effects. The gene for this receptor (TNF-RSF1B) has, moreover, been implicated in hypertension, elevated cholesterol and insulin resistance. TNFRSF1B is thus a worthy candidate in studies of the genetic basis of CAD. We therefore conducted a case-control study of a microsatellite marker with five alleles (CA13-CA17) in intron 4 of TNFRSF1B in 1006 well-characterized white patients with angiographically confirmed CAD and a control group of 183 healthy subjects. We found a strong association of the TNFRSF1B marker with CAD (chi2=40, P=0.00000069). The frequency of the CA16 allele was 33% in CAD vs. 21% in control (odds ratio, OR, to have CAD for presence vs. absence of CA16 allele in CA16 homozygotes was 4.5, 95% CI 2.1-9.4, P<0.0001; in CA16 heterozygotes OR was 1.3, 95% CI 0.94-1.89, P=0.10). The frequency of the major allele (CA15) was 43% in CAD vs. 56% in controls (in CA15 homozygotes OR 0.33, 95% CI 0.20-0.52, P<0.0001; in heterozygotes OR 0.41, 95% CI 0.26-0.63, P<0.0001). In a stepwise logistic regression model the CA16 allele was significantly associated with overweight (OR 1.44, 95% CI 1.0-1.9, P=0.027). Apolipoprotein A-I was elevated (P<0.0001), as was high-density lipoprotein (P=0.098), and severity of angina was decreased (P=0.024) as a function of genotype. Plasma soluble (s) TNF-R2 was 5.1 +/- 0.1 ng/ml in CAD vs. 3.2 +/- 0.1 in control (P<0.0001), 5.2 +/- 0.1 in the presence vs. 4.6 +/- 0.2 in the absence of vessel disease (P=0.009), and rose with increasing severity of angina: 4.2 +/- 0.2 (no angina), 5.0 +/- 0.1 (stable angina), 5.4 +/- 0.2 (unstable angina; P=0.003). sTNF-R2 was correlated with age, cholesterol, creatinine, fibrinogen, transforming growth factor beta and homocysteine and was influenced by TNFRSF1B genotype. Thus genetic variation in or near the TNFRSF1B locus may predispose to CAD.
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PMID:Tumor necrosis factor receptor 2 gene (TNFRSF1B) in genetic basis of coronary artery disease. 1135 33

In human hypertension (HT) plasma tumor necrosis factor (TNF-alpha) and soluble TNF receptor 2 fragment (sTNF-R2) are increased, and the TNF-R2 gene (TNFRSF1B) has been implicated. Therefore, we measured Tnfr2 mRNA in kidney, adrenal, heart, and aorta from rats with ACTH-induced, corticosterone-induced, and spontaneous HT (SHR), and tested the effect of blockade of TNF-alpha by a recombinant TNF-R2 fragment (huTNFR:Fc) on development of HT in the ACTH model. Tnfr2 mRNA was quantified by real-time polymerase chain reaction, as were internal controls, beta-actin, and glyceraldehyde-3-phosphate dehydrogenase mRNA. The results showed no differences in tissue Tnfr2 mRNA between HT and control rats. The ACTH-induced HT was not affected by huTNFR:Fc coadministration. The findings thus offer no support for altered Tnfr2 expression in the rat models studied.
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PMID:Tumor necrosis factor receptor 2 mRNA in rat models of hypertension. 1287 76

Depression has frequently been reported to be associated with other physical diseases and changes in the cytokine system. We aimed to investigate associations between a medical history of depression, its comorbidities and cytokine plasma levels in the Bavarian Nutrition Survey II (BVS II) study sample and in patients suffering from an acute depressive episode. The BVS II is a representative study of the Bavarian population aged 13-80years. The disease history of its 1050 participants was assessed through face-to-face interviews. A sub-sample of 568 subjects and 62 additional acutely depressed inpatients of the Max Planck Institute of Psychiatry participated in anthropometric measurements and blood sampling. Tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptor (sTNF-R) p55 and sTNF-R p75 plasma levels were measured using enzyme-linked immunosorbent assays. A history of depression was associated with a higher incidence of high blood pressure, peptic ulcer, dyslipoproteinemia, osteoporosis, allergic skin rash, atopic eczema and thyroid disease. Within the BVS II sample, participants with a history of depression differed from subjects who had never had depression with regard to sTNF-R p55 and sTNF-R p75 levels even when controlling for age, BMI and smoking status. Acutely depressed inpatients showed even higher levels of sTNF-R p55 and sTNF-R p75 than subjects in the normal population. TNF-alpha levels were also significantly elevated in acutely depressed patients. These results confirm earlier studies regarding the comorbidities of depression and support the hypothesis that activation of the TNF-alpha system may contribute to the development of a depressive disorder.
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PMID:Depression, comorbidities and the TNF-alpha system. 1850 18

In the Sabra rat, oxidative stress (OS) and inflammation precede the development of hypertension. Inhibition of the phagocytic NADPH oxidase attenuates the rise in blood pressure. The present study was set to identify possible priming agents for this enzyme and to test the hypothesis that the phagocytic NADPH oxidase contributes to OS and inflammation. Sabra salt-sensitive and Sabra salt-resistant rats were salt loaded or provided regular chow for 60 days with or without apocynin to inhibit NADPH oxidase. Levels of interleukin 6, tumor necrosis factor-alpha, and interferon-gamma served as indices of inflammation. Extracellular and intracellular levels of the polymorphonuclear leukocyte tumor necrosis factor-alpha receptors (p55 and p75) were assessed by flow cytometry in young and adult rats. NADPH oxidase activity and expression of p47phox were measured in polymorphonuclear leukocytes and aortic rings. Malondialdehyde and carbonylated fibrinogen served as indices of OS. Inflammatory and OS indices excluding interferon-gamma were higher in the hypertensive state and reduced by apocynin. Levels of malondialdehyde and tumor necrosis factor-alpha were elevated already in the prehypertensive state. No differences were found in the levels of p75. The extracellular expression of p55 was higher in adult Sabra salt-resistant compared with Sabra salt-sensitive rats (7.46+/-2.2% versus 2.1+/-0.5%; P<0.05), whereas levels of the intracellular p55 were higher in adult Sabra salt-sensitive rats (3.2+/-2% versus 1.1+/-0.5%; P<0.05). In young normotensive rats, the extracellular levels of p55 were higher in Sabra salt-sensitive compared with Sabra salt-resistant rats (10.6+/-5.2% versus 2.9+/-1.5%; P<0.01). Tumor necrosis factor-alpha plays a role in activation of the polymorphonuclear leukocyte NADPH oxidase, thereby contributing to systemic OS, inflammation, and the development of hypertension in this model.
Hypertension 2010 Feb
PMID:Tumor necrosis factor-alpha: a possible priming agent for the polymorphonuclear leukocyte-reduced nicotinamide-adenine dinucleotide phosphate oxidase in hypertension. 2006 51