Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although endothelial nitric oxide synthase (eNOS) is a constitutively expressed enzyme, its expression is regulated by a number of biophysical, biochemical, and hormonal stimuli, both under physiological conditions and in pathology. This review summarizes the recent findings in this field. Shear stress, growth factors (such as transforming growth factor-beta, fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor), hormones (such as estrogens, insulin, angiotensin II, and endothelin 1), and other compounds (such as lysophosphatidylcholine) upregulate eNOS expression. On the other hand, the cytokine tumor necrosis factor-alpha and bacterial lipopolysaccharide downregulate the expression of this enzyme. The growth status of cells, the actin cytoskeleton, and NO itself are also important regulators of eNOS expression. Both transcriptional and posttranscriptional mechanisms are involved in the expressional regulation of eNOS. Different signaling pathways are involved in the regulation of eNOS promoter activity and eNOS mRNA stability. Changes in eNOS expression and activity under pathophysiological conditions and the pharmacological modulation of eNOS expression are subject of a subsequent brief review (part 2) to be published in the next issue of this journal.
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PMID:Physiological mechanisms regulating the expression of endothelial-type NO synthase. 1222 83

1. The formation of NO from endothelial nitric oxide synthase (eNOS) in rat superior mesenteric artery rings was dependent on extracellular L-arginine, and was optimal at a concentration of L-arginine close to the plasma level (carbachol-stimulated NO: control 15.7+/-0.9, L-arginine 100 micro M 22.8+/-1.3 nM). 2. Enhancement of NO output by L-arginine was stereospecific, required the cationic amino-acid transporter and was dependent on caveolin. 3. Induction of inducible nitric oxide synthase (iNOS) impaired the stimulated NO synthesis from eNOS (100 nM carbachol-stimulated NO: control 5.7+/-0.6, iNOS 0.3+/-0.3 nM). 4. The interaction between iNOS and eNOS was reversed by the superoxide scavenger MnTMPyP. Impairment of eNOS by iNOS was also prevented by L-arginine 100 micro M administered simultaneously with carbachol, but not by L-arginine administered during incubation with lipopolysaccharide. 5. These data provide functional evidence that supplementing L-arginine from the extracellular medium optimises the formation of NO from eNOS and suggests that the impairment of eNOS by iNOS is caused by excess formation of superoxide by NO synthase, which can be prevented by L-arginine. These results provide an explanation for the observations that extracellular L-arginine can enhance endothelium function only when the endothelium is impaired or when iNOS has been induced.
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PMID:Extracellular L-arginine is required for optimal NO synthesis by eNOS and iNOS in the rat mesenteric artery wall. 1292 36

We tested the hypothesis that metalloendopeptidase inhibition using phosphoramidon during induction of endotoxemia 24 h later would down-regulate the protein expression of myocardial inducible nitric oxide synthase (iNOS) and phosphorylation of p38-mitogen-activated protein kinase (p38-MAPK). Male Sprague-Dawley rats (350-400 g) were randomly divided into sham-treated and LPS-treated groups (Escherichia. coli lipopolysaccharide [LPS] 2 mg/kg bolus + 2 mg/kg infusion for 30 min). The animals in each group were further subdivided into vehicle- and phosphoramidon (1 mg/kg bolus)-treated subgroups. Blood and heart samples were collected at 2- and 24-h postendotoxemia/phosphoramidon treatment. LPS at 2 h after its administration produced a significant decrease in mean arterial pressure that was blocked by phosphoramidon treatment. LPS at 2 and 24 h produced a significant elevation in the concentration of left ventricular endothelin-1 (ET-1) both in heart and plasma as compared with control group. This LPS-induced left ventricular ET-1 elevation at 24 h was significantly reduced by phosphoramidon. No significant alterations were observed in the myocardial protein expression of preproET-1, iNOS, and eNOS at 2 h post LPS. In 24-h post treatment groups phosphoramidon upregulated the expression of myocardial preproET-1 protein both in control and endotoxemic rat groups. Also, LPS-induced upregulated protein expression of myocardial-inducible nitric oxide synthase and increased levels of nitric oxide byproducts at 24 h were blocked by phosphoramidon. Phosphoramidon inhibited LPS-induced down-regulated expression of myocardial endothelial nitric oxide synthase and upregulated p38-MAPK phosphorylation. These results indicated that inhibition of metalloendopeptidase during induction of endotoxemia could regulate the phosphorylation of myocardial p38-MAPK and iNOS protein expression at 24-h post endotoxemia. We concluded that inhibition of metalloendopeptidases during early endotoxemia not only decreased the biosynthesis of ET-1 in heart locally but also simultaneously down-regulated myocardial protein expression of iNOS and p38-MAPK phosphorylation in the later stage of endotoxemia.
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PMID:Metalloendopeptidase inhibition regulates phosphorylation of p38-mitogen-activated protein kinase and nitric oxide synthase in heart after endotoxemia. 1450 53

Sepsis and septic shock are important causes of morbidity and lethality in noncoronary intensive care units. Circulating levels of high-density lipoproteins (HDLs) are reduced in sepsis/septic shock, and the magnitude of this reduction is positively correlated with the severity of the illness. The mechanisms underlying this phenomenon are incompletely understood, although increased levels of several acute-phase proteins, including serum amyloid A (SAA) and secretory phospholipase A2 (sPLA2), may contribute to the decrease in plasma HDLs. It has been suggested that HDLs possess anti-inflammatory properties and, hence, may play a crucial role in innate immunity by regulating the inflammatory response as well as being capable of reducing the severity of organ injury in animals and patients with septic shock. These protective effects of HDLs are mediated mainly via (a) lipopolysaccharide (LPS) binding and neutralization, (b) the HDL-associated enzymes, plasma paraoxonase (PON1) and platelet-activating factor acetylhydrolase (PAF-AH), which protect low-density lipoproteins against peroxidative damage, (c) inhibition of the expression of endothelial cell adhesion molecules and release of proinflammatory cytokines, which prevents inflammatory cell infiltration and subsequent multiple organ dysfunction, and (d) stimulation of the expression of endothelial nitric oxide synthase (eNOS). Thus, HDL exerts potent anti-inflammatory effects, some of which are independent of endotoxin binding and might be useful in the treatment of patients with not only sepsis/septic shock but also other conditions associated with an uncontrolled inflammatory response, such as ischemia-reperfusion injury and hemorrhagic shock.
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PMID:High-density lipoproteins in sepsis and septic shock: metabolism, actions, and therapeutic applications. 1477 33

Magnesium supplementation has been reported to prevent cardiovascular diseases through the decrease of plasma lipids and to improve endothelial function in patients with coronary artery disease. In the present work, we evaluated whether high magnesium concentrations can directly affect the function of cultured endothelial cells, which play a crucial role in maintaining the functional integrity of the vascular wall. We cultured human umbilical vein endothelial cells for various times in media containing different concentration of magnesium (range 2 to 10 mM) and compared them to the corresponding controls (1 mM Mg). High Mg concentrations stimulated endothelial proliferation, enhanced the motogenic response to angiogenic factors and attenuated the response to lipopolysaccharide (LPS). In addition, we demonstrate that high concentrations of magnesium did not modulate the levels of plasminogen activator inhibitor-1, but enhanced the synthesis of nitric oxide, in part through the up-regulation of endothelial nitric oxide synthase. Our results demonstrate a direct role of magnesium in maintaining endothelial function. We therefore anticipate that magnesium may have a protective effect against atherosclerosis and could play a role in promoting the growth of collateral vessels in chronic ischemia. Moreover, because it induces the synthesis of nitric oxide, this cation could be a helpful tool in hypertension as well as in preventing thrombosis.
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PMID:High concentrations of magnesium modulate vascular endothelial cell behaviour in vitro. 1515 8

The endothelial cells (EC) of the microvasculature in the brain form the anatomical basis of the blood-brain barrier (BBB). In the present study, the effects of agents that modify the permeability of a well-established in vitro model of the human BBB were studied. The monolayers formed by confluent human brain microvessel endothelial cell (HBMEC) cultures are impermeable to the macromolecule tracer horseradish peroxidase (HRP) and have high electrical resistance. Exposure of HBMEC to various cytokines including TNF-alpha, IL-1beta, interferon gamma (IFN-gamma), or lipopolysaccharide (LPS) decreased transendothelial electrical resistance (TEER) mainly by increasing the permeability of the tight junctions. Primary cultures of HBMEC express endothelial nitric oxide synthase (eNOS) and produce low levels of NO. Treatment with the NO donors sodium nitroprusside (SNP) and DETA NONOate or the cGMP agonist 8-Br-cGMP significantly increased monolayer resistance. Conversely, inhibition of soluble guanylyl cyclase with ODQ rapidly decreased the resistance, and pretreatment of HBMEC with Rp-8-CPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, partially prevented the 8-Br-cGMP-induced increase in resistance. Furthermore, NO donors and 8-Br-cGMP could also reverse the increased permeability of the monolayers induced by IL-1beta, IFN-gamma, and LPS. These results indicate that NO can decrease the permeability of the human BBB through a mechanism at least partly dependent on cGMP production and cGMP-dependent protein kinase activation.
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PMID:Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. 1553 Aug 83

Cardiopulmonary bypass (CPB) is associated with an inflammatory process that leads to lung injury. In this study, we hypothesized that inhaled nitric oxide (INO) possesses the ability to modulate CPB-induced inflammation. Fifteen male pigs were randomly divided into 3 groups: Sham, CPB+LPS (CPB and lipopolysaccharide), and CPB+LPS+INO. INO (20 parts per million) was administered for 24 h after anesthesia. CPB was performed for 90 min, and LPS was infused (1 microg/kg) after CPB. Bronchoalveolar lavage (BAL) fluid and blood were collected at T0 (before CPB), at 4 h, and at 24 h. At 24 h, BAL interleukin-8 (IL-8) levels were not increased as expected in the CPB+LPS group compared with the Sham group, but they were reduced significantly in the CPB+LPS+INO group. Cell hypo reactivity observed in the groups receiving LPS also seemed to downregulate endothelial nitric oxide synthase NOS protein expression relative to the Sham group. Nitrite and nitrate (NOx) concentrations were decreased significantly in the groups without INO. Moreover, animals treated with INO showed higher rates of pulmonary apoptosis compared with their respective controls. These results demonstrate that NOx production is reduced after CPB and that INO acts on the inflammatory process by diminishing neutrophils and their major chemoattractant, IL-8. INO also increases cell apoptosis in the lungs under inflammatory conditions, which may explain, in part, how it resolves pulmonary inflammation.
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PMID:The anti-inflammatory effect of inhaled nitric oxide on pulmonary inflammation in a swine model. 1587 Aug 39

During endotoxemia, liver microcirculation disruption is characterized by a hypersensitivity to the constrictor effects of endothelin 1 (ET-1). The shift of ET-1-mediated effects toward vasoconstriction may result from depressed ET-1-mediated vasodilation through decreased ET-1-induced nitric oxide (NO) production. We have previously shown that lipopolysaccharide (LPS) pretreatment abrogates ET-1-induced endothelial nitric oxide synthase (eNOS) translocation, but its effects on eNOS activation are yet to be determined. Our aim was to assess the effects of LPS on ET-1-mediated eNOS activation in hepatic sinusoidal endothelial cells (SECs) and to investigate the molecular mechanisms involved. SECs were treated with LPS (100 ng/mL) for 6 hours followed by 30 minutes ET-1 (10 nmol/L) stimulation. LPS significantly inhibited ET-1-mediated eNOS activation. This inhibition was associated with upregulation of Caveolin-1 (CAV-1) and a shift in ET-1-mediated eNOS phosphorylation from an activation (Ser1177) to an inhibition (Thr495). LPS treatment has been shown to induce ET-1 expression and secretion from endothelial cells. We therefore investigated the role of endogenous ET-1 in the inhibition of ET-1 activation of eNOS after LPS. Antagonizing ET-1 effects and blocking its activation in LPS pretreated SECs decreased the LPS-induced overexpression of CAV-1 as well as the inhibition of ET-1-induced NOS activity. Furthermore, 6 hours of ET-1 treatment exerted the same effects on eNOS activity, phosphorylation, and CAV-1 expression as LPS treatment. In conclusion, LPS-induced suppression of ET-1-mediated eNOS activation is ET-1 dependent and suggest a pivotal role of CAV-1 in eNOS induction inhibition under stress.
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PMID:LPS inhibits endothelin-1-induced endothelial NOS activation in hepatic sinusoidal cells through a negative feedback involving caveolin-1. 1637 54

Overproduction of nitric oxide by inducible nitric oxide synthase contributes to the progression of cardiovascular disease. We investigated the effects of azelnidipine and other Ca2+-channel blockers on nitric oxide production by cultured aortic smooth muscle cells isolated from Wistar rats and human umbilical vein endothelial cells (HUVECs), using the Griess reaction and oxyhemoglobin method. Release of lactic dehydrogenase (LDH) was measured to evaluate cell damage, and immunohistochemistry was performed to examine the expression of inducible nitric oxide synthase and nitrotyrosine protein. Azelnidipine and other Ca2+-channel blockers inhibited the release of nitric oxide induced by lipopolysaccharide plus interferon-gamma. Azelnidipine inhibited it most potently among the Ca2+-channel blockers tested (azelnidipine, amlodipine, nifedipine, diltiazem, verapamil, and nicardipine) at a concentration of 10 microM. Longer stimulation with these agents induced the expression of inducible nitric oxide synthase and nitrotyrosine, with an increase of lactic dehydrogenase release, whereas azelnidipine suppressed these changes. In human umbilical vein endothelial cells, azelnidipine enhanced basal nitric oxide production by endothelial nitric oxide synthase. In conclusion, azelnidipine potently inhibited the induction of inducible nitric oxide synthase and then nitric oxide production in vascular smooth muscle cells, while enhancing constitutive nitric oxide production by endothelial cells. Azelnidipine may inhibit nitrotyrosine expression and cell damage caused by overproduction of nitric oxide, suggesting a mechanism for its cardiovascular protective effect.
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PMID:Comparative effects of azelnidipine and other Ca2+-channel blockers on the induction of inducible nitric oxide synthase in vascular smooth muscle cells. 1649 72

Human endothelial nitric oxide synthase (eNOS) plays a crucial role in maintaining blood pressure homeostasis and vascular integrity. eNOS gene expression may be upregulated by a signaling pathway, including PI-3Kgamma--> Jak2--> MEK1 --> ERK1/2--> PP2A. It remains unclear whether other mitogen-activated protein kinase (MAPK) family members, such as JNK, p38 kinase, and ERK5/BMK1, also modulate eNOS gene expression. Our purpose, therefore, is to shed light on the effect of the p38 MAPK signaling pathway on the regulation of eNOS promoter activity. The results showed that a red fluorescent protein reporter gene vector containing the full length of the human eNOS promoter was first successfully constructed, expressing efficiently in ECV304 cells with the characteristics of real time observation. The wild-types of p38alpha, p38beta, p38gamma, and p38delta signal molecules all markedly downregulated promoter activity, which could be reversed by their negative mutants, including p38alpha (AF), p38beta (AF), p38gamma (AF), and p38delta (AF). Promoter activity was also significantly downregulated by MKK6b (E), an active mutant of an upstream kinase of p38 MAPK. The reduction in promoter activity by p38 MAPK could be blocked by treatment with a p38 MAPK specific inhibitor, SB203580. Moreover, the activation of endogenous p38 MAPK induced by lipopolysaccharide resulted in a prominent reduction in promoter activity. These findings strongly suggest that the activation of the p38 MAPK signaling pathway may be implicated in the downregulation of human eNOS promoter activity.
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PMID:Downregulation of human endothelial nitric oxide synthase promoter activity by p38 mitogen-activated protein kinase activation. 1716 42


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