Downregulation of Endothelial Constitutive Nitric Oxide Synthase Expression by Lipopolysaccharide

Lu, Jia-ling; Schmiege, Lorenz M.; Li, Kuo; Liao, James C.

doi:10.1006/bbrc.1996.1121

Cited by 99 publications

(70 citation statements)

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“…Impaired endothelium-dependent vasodilation has been found within 1 to 2 h after endotoxemia in humans (Bhagat et al, 1996) and in animal models . The mechanisms implicated in LPS-mediated impairment of endothelium-dependent vasodilation include inhibition of eNOS enzymatic activity and/or down-regulation of eNOS expression (Lu et al, 1996). Alterations in eNOS have thus been found at both early and late time points after cellular exposure to endotoxin.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, inhibition of iNOS worsened rather than improved acute respiratory distress syndrome in animal models (Cobb et al, 1999). Likewise, endotoxin down-regulates eNOS in renal arteries, leading to impaired endothelium-dependent vasodilation (Lu et al, 1996), and in rodent models of shock, resulting in NO derived from iNOS becoming the major source of this vasodilator (Lu et al, 1996). Finally, septic shock studies involving iNOS knockout mice have demonstrated that such animals have a much greater mortality rate than their wild-type counterparts, again underscoring the importance of iNOS in septic shock (Cobb et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…In septic shock, inhibition of the activity of the constitutive endothelial cell isoform of nitric-oxide synthase (eNOS) precedes the induction of iNOS (Lu et al, 1996). Moreover, down-regulation of eNOS occurs at time points similar to those where iNOS induction is seen.…”

mentioning

confidence: 99%

“…Even so, results from iNOS knockout mice have been controversial, with some studies reporting reduced endotoxin-related hypotension and others indicating no effects or even detrimental outcomes (Nicholson et al, 1999). Furthermore, the extensive evaluation of selective inhibitors for iNOS, such as aminoguanidine and N-iminoethyl-L-lysine in models of shock, have likewise been disappointing and controversial (Thiemermann et al, 1995;Parratt, 1997).In septic shock, inhibition of the activity of the constitutive endothelial cell isoform of nitric-oxide synthase (eNOS) precedes the induction of iNOS (Lu et al, 1996). Moreover, down-regulation of eNOS occurs at time points similar to those where iNOS induction is seen.…”

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confidence: 99%

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A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock

Cuzzocrea¹,

Mazzon²,

Paola³

et al. 2006

J Pharmacol Exp Ther

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The aim of the present study was to assess the relative contributions of peroxynitrite formation following induction of nitric-oxide synthase (iNOS) in the pathophysiology of endotoxin-induced shock in the rat. To this end, we used a selective inhibitor of iNOS, N- (3-(aminomethyl)benzyl)acetamidine (1400W), and a peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTTPs). Intravenous (i.v.) administration of Escherichia coli lipopolysaccharide (LPS; 4 mg/kg) elicited a timedependent fall in mean arterial pressure as well as liver, renal, and pancreatic tissue damage. 1400W (3-10 mg/kg i.v.) administered 30 min before LPS delayed the development of hypotension but did not improve survival. On the other hand, FeTTPs administered (10 -100 mg/kg i.v.) inhibited in a dose-dependent manner LPS-induced hypotension, tissue injury, and improved mortality rate. In separate experiments, rats were treated with LPS (4 mg/kg) or saline for control, and their aortas were isolated and placed in organ baths 2 h later. Tissues from LPS-treated rats had significant inhibition of contractile activity to phenylephrine as well as a significantly impaired relaxation response to acetylcholine. FeTPPs, when administered (100 mg/kg i.v.) 1 h before LPS, prevented the LPS-induced aortic contractile and endothelial dysfunction. These results demonstrate that nitric oxide-derived peroxynitrite formation plays an important role in this model of endotoxemia. Our results also suggest that use of an iNOS inhibitor in this setting has little beneficial effect in part because, in the presence of a failing eNOS system, some NO is needed to maintain adequate organ function.Severe hypotension, development of hyporeactivity to vasopressors, and ultimately, progressive multiple organ dysfunction characterize the pathogenesis of Gram-negative bacterial endotoxic shock (Siegel et al., 1967). The cause of the systemic vasodilation associated with shock, in particular, is still unclear, although overproduction of the potent vasodilator nitric oxide (NO) from the inducible form of nitric-oxide synthase (iNOS) has been implicated (Nathan, 1992;Thiemermann, 1994;Rixen et al., 1997). Even so, results from iNOS knockout mice have been controversial, with some studies reporting reduced endotoxin-related hypotension and others indicating no effects or even detrimental outcomes (Nicholson et al., 1999). Furthermore, the extensive evaluation of selective inhibitors for iNOS, such as aminoguanidine and N-iminoethyl-L-lysine in models of shock, have likewise been disappointing and controversial (Thiemermann et al., 1995;Parratt, 1997).In septic shock, inhibition of the activity of the constitutive endothelial cell isoform of nitric-oxide synthase (eNOS) precedes the induction of iNOS (Lu et al., 1996). Moreover, down-regulation of eNOS occurs at time points similar to those where iNOS induction is seen. Collectively, these results indicate that the beneficial effects of NO from eNOS are probably lost ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock

Cuzzocrea¹,

Mazzon²,

Paola³

et al. 2006

J Pharmacol Exp Ther

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“…Notably, we and others have shown that hypoxia significantly downregulates eNOS gene expression in ECs, with major contributions from the posttranscriptional downregulation of eNOS mRNA expression (9)(10)(11). In addition, models of proliferation/injury (12), tumor necrosis factor alpha (TNF-␣) treatment (13,14), and exposure to lipopolysaccharide (15) or high levels of oxidized low-density lipoprotein (16) all decrease eNOS steady-state mRNA expression in cultured ECs in a manner dependent, in major part, on changes in eNOS mRNA stability.…”

mentioning

confidence: 99%

Active Stabilization of Human Endothelial Nitric Oxide Synthase mRNA by hnRNP E1 Protects against Antisense RNA and MicroRNAs

Robb

Tai

et al. 2013

Molecular and Cellular Biology

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Human endothelial nitric oxide synthase (eNOS) mRNA is highly stable in endothelial cells (ECs). Posttranscriptional regulation of eNOS mRNA stability is an important component of eNOS regulation, especially under hypoxic conditions. Here, we show that the human eNOS 3= untranslated region (3= UTR) contains multiple, evolutionarily conserved pyrimidine (C and CU)-rich sequence elements that are both necessary and sufficient for mRNA stabilization. Importantly, RNA immunoprecipitations and RNA electrophoretic mobility shift assays (EMSAs) revealed the formation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1)-containing RNP complexes at these 3=-UTR elements. Knockdown of hnRNP E1 decreased eNOS mRNA half-life, mRNA levels, and protein expression. Significantly, these stabilizing RNP complexes protect eNOS mRNA from the inhibitory effects of its antisense transcript sONE and 3=-UTR-targeting small interfering RNAs (siRNAs), as well as microRNAs, specifically, hsa-miR-765, which targets eNOS mRNA stability determinants. Hypoxia disrupts hnRNP E1/eNOS 3=-UTR interactions via increased Akt-mediated serine phosphorylation (including serine 43) and increased nuclear localization of hnRNP E1. These mechanisms account, at least in part, for the decrease in eNOS mRNA stability under hypoxic conditions. Thus, the stabilization of human eNOS mRNA by hnRNP E1-containing RNP complexes serves as a key protective mechanism against the posttranscriptional inhibitory effects of antisense RNA and microRNAs under basal conditions but is disrupted under hypoxic conditions.

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Variants in TNF and NOS3 (eNOS) genes associated with sepsis in adult patients

Özkan

Günay

Şener

et al. 2021

The Journal of Gene Medicine

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Background Sepsis is a life‐threatening condition caused by a dysregulated host response to infections and is a leading cause of death in hospitalized patients. The present study aimed to elucidate the possible association between sepsis and the tumor necrosis factor (TNF) gene –308G/A (rs1800629) polymorphism, as well as endothelial nitric oxide synthase (eNOS, NOS3) gene –786T/C (rs2070744), 4a/4b (27 bp‐VNTR in intron 4, rs61722009) and 894G/T (Glu298Asp, rs1799983) polymorphisms. Methods In total, 188 septic adult cases and 188 healthy controls were enrolled. Genomic DNAs from the controls and patients were analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. Results There were significant associations between the G/G genotype and G allele of the TNF –308G/A (rs1800629) polymorphism in the sepsis group (p < 0.001). The presence of the T/C genotype (p = 0.002) and C allele (p = 0.001) of the –786T/C (rs2070744) was markedly associated with an increased risk of sepsis. However, no significant associations were found with 4a/4b (27 bp‐VNTR in intron 4, rs61722009) and 894G/T (Glu298Asp, rs1799983) polymorphisms. Higher 4bGC and lower 4bTT haplotype frequencies were associated with sepsis. Conclusions Our results strongly suggest that TNF gene (−308G/A, rs1800629) and NOS3 gene –786T/C (rs2070744) polymorphisms may modify individual susceptibility to sepsis in the Turkish population.

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Downregulation of Endothelial Constitutive Nitric Oxide Synthase Expression by Lipopolysaccharide

Cited by 99 publications

References 0 publications

A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock

A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock

Active Stabilization of Human Endothelial Nitric Oxide Synthase mRNA by hnRNP E1 Protects against Antisense RNA and MicroRNAs

Variants in TNF and NOS3 (eNOS) genes associated with sepsis in adult patients

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