Anaphylactic shock depends on PI3K and eNOS-derived NO

Cauwels, Anje

doi:10.1172/jci25426

Cited by 123 publications

(133 citation statements)

References 55 publications

(87 reference statements)

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“…[22][23][24] Moreover, acute hypotension and lethality after antigen challenge and PAF injection entirely depend on the PI3K/Akt/eNOS pathway. 26 Our results also showed that inhibition of eNOS action by genetic or pharmacological manipulation in S1pr2 -/-mice markedly improved vascular leakage, hypotension and survival rate after antigen challenge, thus abrogating the effects of S1pr2 deficiency (Fig 3 and Fig E5). All these observations together indicate that S1P 2 provides a protective effect against vascular barrier disruption largely by suppressing eNOS.…”

Section: Discussionsupporting

confidence: 70%

“…32 However, the previous study 26 showed that a specific inhibitor of soluble guanylate cyclase or genetic deletion of soluble guanylate cyclase-α1, a major isoform in the vasculature, did not protect mice from PAF-induced lethality, suggesting that NO might mediate shock in a manner independent of cGMP. In addition to guanylate cyclase-cGMP, NO may affect biological processes through causing S-nitrosylation of proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, anaphylactic shock has been shown to depend on eNOS activation mediated by endothelial G q/11 and phosphatidylinositol 3-kinase (PI3K)-Akt. 26,27 We recently found that endogenous S1P 2 mediates inhibition of Akt in EC, 10 unlike S1P 1 which stimulates eNOS via Akt. 28 These observations raise the possibility that S1P 2 might suppress eNOS through inhibition of Akt, exerting a Cui 8 rescue effect on vascular hyperpermeability.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

Chen¹,

Okamoto²,

Yoshioka³

et al. 2013

Journal of Allergy and Clinical Immunology

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

Chen¹,

Okamoto²,

Yoshioka³

et al. 2013

Journal of Allergy and Clinical Immunology

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“…A recent experiment with mice triggered anaphylactic shock by exposing the mice to an injection containing aluminum hydroxide and pertussis toxin [74]. This resulted in the excess synthesis of NO by eNOS, and a subsequent signaling cascade, mediated by the phosphatidyl inositol-3 kinase (PI3K) pathway.…”

Section: Mechanisms Of Aluminum and Mercury Toxicitymentioning

confidence: 99%

Empirical Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen Exposure

Seneff

Davidson²,

Liu

2012

Entropy

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Autism is a condition characterized by impaired cognitive and social skills, associated with compromised immune function. The incidence is alarmingly on the rise, and environmental factors are increasingly suspected to play a role. This paper investigates word frequency patterns in the U.S. CDC Vaccine Adverse Events Reporting System (VAERS) database. Our results provide strong evidence supporting a link between autism and the aluminum in vaccines. A literature review showing toxicity of aluminum in human physiology offers further support. Mentions of autism in VAERS increased steadily at the end of the last century, during a period when mercury was being phased out, while aluminum adjuvant burden was being increased. Using standard log-likelihood ratio techniques, we identify several signs and symptoms that are significantly more prevalent in vaccine reports after 2000, including cellulitis, seizure, depression, fatigue, pain and death, which are also significantly associated with aluminum-containing vaccines. We propose that children with the autism diagnosis are especially vulnerable to toxic metals such as aluminum and mercury due to insufficient serum sulfate and glutathione. A strong correlation between autism and the MMR (Measles, Mumps, Rubella) vaccine is also observed, which may be partially explained via an increased sensitivity to acetaminophen administered to control fever.

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“…Agonists activate eNOS through multiple mechanisms: phosphorylation/ dephosphorylation of specific residues, interaction with different proteins, S-nitrosylation, and specific subcellular localization (1,(3)(4)(5)(6)(7). Agonists such as platelet-activating factor (PAF) and VEGF phosphorylate eNOS via Akt (8,9). Despite advances in our understanding of the biochemistry of eNOS, the mechanisms by which these molecular modifications determine the functional outcome of eNOS activation remain unexplored.…”

mentioning

confidence: 99%

Internalization of eNOS and NO delivery to subcellular targets determine agonist-induced hyperpermeability

Sánchez

Rana²,

Kim³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The molecular mechanisms of endothelial nitric oxide synthase (eNOS) regulation of microvascular permeability remain unresolved. Agonist-induced internalization may have a role in this process. We demonstrate here that internalization of eNOS is required to deliver NO to subcellular locations to increase endothelial monolayer permeability to macromolecules. Using dominant-negative mutants of dynamin-2 (dyn2K44A) and caveolin-1 (cav1Y14F), we show that anchoring eNOS-containing caveolae to plasma membrane inhibits hyperpermeability induced by plateletactivating factor (PAF), VEGF in ECV-CD8eNOSGFP (ECV-304 transfected cells) and postcapillary venular endothelial cells (CVEC). We also observed that anchoring caveolar eNOS to the plasma membrane uncouples eNOS phosphorylation at Ser-1177 from NO production. This dissociation occurred in a mutant-and cell-dependent way. PAF induced Ser-1177-eNOS phosphorylation in ECVCD8eNOSGFP and CVEC transfected with dyn2K44A, but it dephosphorylated eNOS at Ser-1177 in CVEC transfected with cav1Y14F. Interestingly, dyn2K44A eliminated NO production, whereas cav1Y14F caused reduction in NO production in CVEC. NO production by cav1Y14F-transfected CVEC occurred in caveolae bound to the plasma membrane, and was ineffective in causing an increase in permeability. Our study demonstrates that eNOS internalization is required for agonist-induced hyperpermeability, and suggests that a mechanism by which eNOS is activated by phosphorylation at the plasma membrane and its endocytosis is required to deliver NO to subcellular targets to cause hyperpermeability.caveolae ͉ endothelial nitric oxide synthase ͉ endothelial permeability ͉ inflammation ͉ protein traffic N itric oxide (NO) is the signal for several outcomes in the control of circulation. Its main source in the cardiovascular system is endothelial (e)NOS. The enzyme is modified by N-myristoylation and palmitoylation, which targets it to the caveolae in the plasma membrane where it is kept in a basal state by binding to caveolin-1 through a consensus site (1, 2). Agonists activate eNOS through multiple mechanisms: phosphorylation/ dephosphorylation of specific residues, interaction with different proteins, S-nitrosylation, and specific subcellular localization (1, 3-7). Agonists such as platelet-activating factor (PAF) and VEGF phosphorylate eNOS via Akt (8, 9). Despite advances in our understanding of the biochemistry of eNOS, the mechanisms by which these molecular modifications determine the functional outcome of eNOS activation remain unexplored.NO derived from eNOS is a key mediator in the hyperpermeability response to PAF and VEGF (7,10,11). We previously showed that eNOS internalization (endocytosis) is a required step in the signaling cascade leading to PAF-induced hyperpermeability (7). In this study, we tested the hypothesis that caveolar internalization of eNOS is a requirement for localized NO production and NO delivery to a subcellular target to cause hyperpermeability. To address this hypothesis, we used ECV-304 cells (...

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Anaphylactic shock depends on PI3K and eNOS-derived NO

Cited by 123 publications

References 55 publications

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

Empirical Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen Exposure

Internalization of eNOS and NO delivery to subcellular targets determine agonist-induced hyperpermeability

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