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)

The decreased expression of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), occurs in response to multiple stimuli in vivo and in cell culture and correlates with various disease states such as hypertension, inflammation, and neurodegenerative disorders. The ability to understand and modulate sGC expression and cGMP levels in any of these conditions could be a valuable therapeutic tool. We demonstrate herein that the c-Jun NH2-terminal kinase JNK II inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) completely blocked the decreased expression of sGCalpha1-subunit mRNA by nerve growth factor (NGF) in PC12 cells. Inhibitors of the ERK and p38 MAPK pathways, PD-98059 and SB-203580, had no effect. SP-600125 also inhibited the NGF-mediated decrease in the expression of sGCalpha1 protein as well as sGC activity in PC12 cells. Other experiments revealed that decreased sGCalpha1 mRNA expression through a cAMP-mediated pathway, using forskolin, was not blocked by SP-600125. We also demonstrate that TNF-alpha/IL-1beta stimulation of rat fetal lung (RFL-6) fibroblast cells resulted in sGCalpha1 mRNA inhibition, which was blocked by SP-600125. Expression of a constitutively active JNKK2-JNK1 fusion protein in RFL-6 cells caused endogenous sGCalpha1 mRNA levels to decrease, while a constitutively active ERK2 protein had no effect. Collectively, these data demonstrate that SP-600125 may influence the intracellular levels of the sGCalpha1-subunit in certain cell types and may implicate a role for c-Jun kinase in the regulation of sGCalpha1 expression.
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PMID:Effects of the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) on soluble guanylyl cyclase alpha1 gene regulation and cGMP synthesis. 1588 53

Insulin resistance and central obesity are often associated with hypertension. The metabolic syndrome is a cluster of these common clinical disorders, and is related with an increased risk for cardiovascular diseases. A number of pro-inflammatory cytokines derived from adipose tissues have been thought to contribute to the development of insulin resistance and accelerated atherosclerosis. Among them, TNF-alpha has been most widely studied; it not only suppresses the insulin signaling, but also elicits vascular inflammation. Indeed, inhibition of TNF-alpha was found to improve insulin resistance in obese rats and reduce the progression of atherosclerosis in apolipoprotein E knockout mice, respectively. These observations demonstrate that TNF-alpha could play a central role in the pathogenesis of insulin resistance and accelerated atherosclerosis in the metabolic syndrome. Considering that the primary goals of treatment for hypertensive patients with the metabolic syndrome are prevention of the development of diabetes and cardiovascular events, anti-hypertensive drugs that have abilities to block the TNF-alpha signaling would be desirable as a first-line therapy for these patients. In the process of the search for such a unique anti-hypertensive drug, we have recently found that azelnidipine, a newly developed and commercially used long-acting dihydropyridine-based calcium antagonist (DHP), inhibited TNF-alpha-induced activator protein-1 activation and interleukin-8 expression in human umbilical vein endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. The concentration of azelnidipine that was found effective in these in vitro-experiments is well within the therapeutic range. Since endothelial cells do not possess voltage-operated L-type calcium channels, these observations suggest that the beneficial effects of azelnidipine are not likely due to calcium channel blocking property, but due to its unique anti-oxidative ability. Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension. In this paper, we would like to hypothesize that due to its unique TNF-alpha signal modulatory, anti-oxidative property, azelnidipine may be a promising DHP that targets diabetes and cardiovascular diseases in hypertensive patients with the metabolic syndrome.
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PMID:Unique atheroprotective property of azelnidipine, a dihydropyridine-based calcium antagonist. 1589 34

Hypertension during preeclampsia is associated with an increase in plasma levels of tumor necrosis factor (TNF)-alpha, a cytokine known to contribute to endothelial dysfunction. Recently, our laboratory reported that a 2-fold increase in plasma TNF-alpha produces hypertension in pregnant rats. Endothelin is also elevated in preeclampsia and endothelin synthesis is enhanced by TNF-alpha. The purpose of this study was to determine the role of endothlelin in mediating TNF-alpha-induced hypertension in pregnant rats. To achieve this goal, TNF-alpha (50 ng/d for 5 days) was infused into control pregnant rats and pregnant rats treated with an endothelin receptor A antagonist, ABT 627 (5 mg/kg per day for 5 days). At day 19 of gestation, arterial pressure was measured and aorta, kidneys, and placentas were harvested. Infusion of TNF-alpha into pregnant rats increased plasma concentration of TNF-alpha (13.5+/-0.8 to 28.0+/-3.7 pg/mL) and arterial pressure (101+/-2 to 122+/-1 mm Hg). The increase in arterial pressure was associated with an increase in preproendothelin mRNA expression in placenta, aorta, and kidneys measured by real-time polymerase chain reaction (PCR). Pretreatment with the endothelin receptor A antagonist completely abolished the blood pressure response to TNF-alpha in pregnant rats (105+/-1 versus 97+/-2 mm Hg). In sharp contrast, the ETA receptor antagonist had no effect on arterial pressure in normal pregnant rats (97+/-2 versus 101+/-2 mm Hg). Moreover, chronic infusion of TNF-alpha had no significant effect on arterial pressure or renal preproendothelin levels in virgin rats. These results suggest an important role for endothelin in mediating TNF-alpha-induced hypertension in pregnant rats.
Hypertension 2005 Jul
PMID:Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats. 1592 30

EXPERIMENTAL OSTEONECROSIS: The authors' experience with experimentally produced femoral capital osteonecrosis in rats is reviewed: incising the periosteum at the base of the neck of the femur and cutting the ligamentum teres leads to coagulation necrosis of the epiphysis. The necrotic debris is substituted by fibrous tissue concomitantly with resorption of the dead soft and hard tissues by macrophages and osteoclasts, respectively. Progressively, the formerly necrotic epiphysis is repopulated by hematopoietic-fatty tissue, and replaced by architecturally abnormal and biomechanically weak bone. The femoral heads lose their smooth-surfaced hemispherical shape in the wake of the load transfer through the hip joint such that, together with regressive changes of the joint cartilage and inflammatory-hyperplastic changes of the articular membrane, an osteoarthritis-like disorder ensues. THERAPEUTIC CHOICES: Diverse therapeutic options are studied to satisfy the different opinions concerning the significance of diverse etiological and pathogenic mechanisms: 1. Exposure to hyperbaric oxygen. 2. Exposure to hyperbaric oxygen and non-weight bearing on the operated hip. 3. Medication with enoxaparin. 4. Reduction of intraosseous hypertension, putting to use a procedure aimed at core decompression, namely drilling a channel through the femoral head. 5. Medication with vascular endothelial growth factor with a view to accelerating revascularization. 6. Medication with zoledronic acid to decrease osteoclastic productivity such that the remodeling of the femoral head is slowed. Glucocorticoid-related osteonecrosis appears to be apoptosis-related, thus differing from the vessel-deprivation-induced tissue coagulation found in idiopathic osteonecrosis. The quantities of TNF-alpha, RANK-ligand and osteoprotegerin are raised in glucocorticoid-treated osteoblasts so that the differentiation of osteoclasts is blocked. Moreover, the osteoblasts and osteocytes of the femoral cortex mostly undergo apoptosis after a lengthy period of glucocorticoid medication.
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PMID:Vasculature deprivation--induced osteonecrosis of the rat femoral head as a model for therapeutic trials. 1599 71

Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha are elevated in preeclamptic women and are thought to be an important link between placental ischemia and endothelial dysfunction. The purpose of this study was to determine the role of TNF in mediating hypertension in response to chronic reductions in uterine perfusion (RUPPs) in pregnant rats. Arterial pressure was significantly higher in RUPP rats (138+/-1 mm Hg) than in pregnant rats (107+/-1 mm Hg). Serum TNF-alpha levels in the RUPP rats were 17+/-4 pg/mL compared with 8+/-1 pg/mL in normal pregnant rats. To determine the long-term effects of a 2- to 3-fold elevation in plasma TNF-alpha on renal and systemic hemodynamics in pregnant rats, we infused TNF-alpha for 5 days at a rate of 50 ng/d during days 14 to 19 of gestation in pregnant rats. Serum levels were 7+/-2 pg/mL in the control pregnant rats and 14+/-2 pg/mL in the TNF-alpha-treated pregnant rats. Mean arterial pressure was higher in the TNF-alpha-treated pregnant rats (123+/-3 mm Hg) compared with pregnant controls (96+/-3 mm Hg) at day 19 of gestation. TNF-alpha increased renal vascular resistance in pregnant rats by 182%. Renal plasma flow was 5.4+/-1.2 mL/min in the TNF-alpha-treated group and 9.2+/-1.6 mL/min in the control group. Glomerular filtration rate was 1.7+/-0.4 mL/min in the TNF-alpha-treated group and 2.6+/-0.4 mL/min in the control group. In summary, these data suggest that TNF-alpha may play an important role in mediating the increased arterial pressure in response to chronic RUPPs in pregnant rats.
Hypertension 2005 Oct
PMID:Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of tumor necrosis factor-alpha. 1614 82

We examined the effect of negative affect on changes in stimulated secretion of cytokines by blood monocytes and determined whether insulin resistance (IR), as indexed by the Homeostasis Model Assessment (HOMA), moderated these associations in 58 healthy men (aged 18-65 years). Blood samples and ratings of negative affect were collected at rest and 15min following subjects' participation in the Anger Recall Interview (ARI). Assessment of lipopolysaccharide (LPS)-stimulated secretion of IL-1beta, IL-6, and TNF-alpha was accomplished by ELISA of supernatant. Regression models controlling for age, body mass index, and race/ethnicity revealed that higher HOMA-IR values were associated with larger stress-induced increases in IL-1beta and TNF-alpha (p<.05). Furthermore, arousal of negative affect during the ARI was differentially associated with stress-induced changes in stimulated secretion of TNF-alpha and IL-6 as a function of HOMA-IR (p<.05). Increases in stimulated cytokine secretion were associated with arousal of negative affect, but only among men with higher HOMA-IR values. Among men with lower HOMA-IR values, arousal of negative affect was associated with diminished cytokine secretion. Collectively, these data suggest that the HOMA-IR moderates the impact that arousal of negative affect has on the ability of blood monocytes to secrete inflammatory cytokines in response to LPS. Stress-induced increases in cytokine secretion among high HOMA-IR men are consistent with the role of inflammation in cardiovascular disease, hypertension, type 2 diabetes as well as the metabolic syndrome and underscore the relevance of negative affect in the etiology of these inflammatory conditions.
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PMID:Increases in stimulated secretion of proinflammatory cytokines by blood monocytes following arousal of negative affect: the role of insulin resistance as moderator. 1628 46

The role of genetic factors in the individual predisposition to develop ischemic stroke has been assessed by previous studies performed both in animal models and in humans. The main goal of the current investigation was to determine the possible contribution of genes encoding procoagulant and inflammatory factors on the occurrence of ischemic stroke in a cohort of young cases and corresponding controls. One hundred and fifteen cases of ischemic stroke were recruited for this study. A detailed clinical assessment, a definite etiologic diagnosis, as well as the presence/absence of known risk factors for ischemic stroke were obtained for each patient. As a control group 180 healthy, unrelated subjects were included. The whole population was screened for polymorphisms belonging to genes encoding FII, FV, alpha-fibrinogen, beta-fibrinogen, GP IIb/IIIa, tumor necrosis factor (TNF)-alpha, interleukin 1-beta. Hypertension was the most important risk factor for ischemic stroke in our cohort [OR = 6.9, confidence interval (CI) 2.9-16.7, P < 0.0001]. Among all genes tested, the TNF-alpha gene variant exerted a significant, independent effect on individual predisposition to ischemic stroke occurrence (OR = 1.8, CI = 1.01-3.3, P < 0.05). Our findings, obtained in a cohort of young Italian patients, may support the existence of a direct contributory role of TNF-alpha, a proinflammatory cytokine protein, in the susceptibility to brain damage.
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PMID:A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study. 1632 93

The chronic elevation in ventricular wall stress secondary to ventricular volume or pressure overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. While initially a compensatory response, the progressive hypertrophy and ventricular dilatation induced by this condition ultimately have a detrimental effect on ventricular function, resulting in heart failure. Fibrillar collagen provides the skeletal framework which interconnects the cardiomyocytes, thereby maintaining ventricular shape and size and contributing to tissue stiffness. Accordingly, these myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. The presence of an abundant, latent matrix metalloproteinase (MMP) population which coexists with myocardial fibrillar collagen has been documented. Thus, the potential for collagen degradation to exceed synthesis exists should there be significant activation of this latent MMP system. Mast cells are known to store and release a variety of biologically active mediators including TNF-alpha and proteases such as tryptase and chymase, which can induce MMP activation. Increased cardiac mast cell density has been implicated in the pathophysiology of human end-stage cardiomyopathy and experimental myocardial infarction, hypertension and chronic volume overload secondary to mitral regurgitation and aorto-caval fistula. The potential role of cardiac mast cells in activating MMPs, which then results in fibrillar collagen degradation and adverse myocardial remodeling secondary to chronic volume and pressure overload will be the subject of this review.
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PMID:Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload. 1637 24

We hypothesized that the downregulation of Cyp2c by tumor necrosis factor (TNF) alpha contributes to hypertension and renal injury in salt-sensitive angiotensin hypertension. Male Sprague-Dawley rats were fed a high-salt diet (8% NaCl), and osmotic minipumps were implanted to deliver angiotensin II for 14 days. Rats were divided into 3 groups: high salt, angiotensin high salt, and angiotensin high salt administered the TNF-alpha blocker, etanercept. Arterial pressure increased from 94+/-5 to 148+/-7 mm Hg during week 1 in the angiotensin high-salt group, whereas etanercept slowed blood pressure elevation during the first week in the treated group (90+/-2 to 109+/-6 mm Hg). After 2 weeks, arterial pressure increased to 156+/-11 mm Hg in the angiotensin high-salt group and 141+/-6 mm Hg in the etanercept-treated group. Albuminuria and proteinuria were significantly elevated in angiotensin high-salt rats and were reduced in the etanercept-treated rats. Urinary monocyte chemoattractant protein-1 excretion significantly increased in the angiotensin high-salt group (275+/-47 versus 81+/-19 ng/day) and was decreased in the etanercept-treated group (153+/-31 ng/day). Angiotensin high-salt rats also had a significant increase in renal monocyte/macrophage infiltration, and this was again attenuated by etanercept treatment. Renal expression of Cyp2c23 decreased, whereas renal epoxide hydrolase expression increased in angiotensin high-salt rats. Etanercept treatment increased Cyp2c23 expression and lowered epoxide hydrolase expression. These data suggest that TNF-alpha contributes to downregulation of Cyp2c23, blood pressure regulation, and renal injury in angiotensin high-salt hypertension.
Hypertension 2006 Mar
PMID:Tumor necrosis factor alpha blockade increases renal Cyp2c23 expression and slows the progression of renal damage in salt-sensitive hypertension. 1641 73

The state of lipid transport function of the blood, blood contents of stable nitrogen metabolites, and proinflammatory cytokines (TNF-a and IL-1b) during therapy with simvastatin were studied in 29 patients receiving combination antihypertensive therapy with angiotensin converting enzyme inhibitors (ACEI) and verapamil. Lipid lowering action of simvastatin was realized just in 1 month of treatment and remained sustained for half a year (average duration). 6 months after addition of simvastatin to antihypertensive therapy substantial (58.4%, p=0.044) rise of plasma content of stable nitrogen metabolites took place. At the same time therapy with metoprolol in a similar group of patients exerted no considerable effect on blood plasma concentration of nitrate and nitrite anions. Lowering of median values of TNF-alpha from 20.13 (12.67-52.80) to 11.34 (3.31-31.29) pg/ml (p<0.0038) was also noted at the background of combination antihypertensive therapy. This happened without distinct affair with degree of lipid lowering action of simvastatin. The results of the study document positive effect of half year treatment of patients with concomitant hypertension and diabetes with simvastatin (10-20 mg/day) in combination with ACEI and verapamil on metabolism of nitric oxide and plasma content of TNF-alpha which realizes independently from degree of hypolipidemic action of simvastatin.
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PMID:[Effect of 6-month therapy with simvastatin on lipid transport function of the blood and the state of endothelium in patients with diabetes and hypertension]. 1647 6


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