Anaphylactic shock depends on Pi3K and eNOS-derived NO

Molecular Pathophysiology and Experimental Therapy Unit, Department for Molecular Biomedical Research, Ghent University, Belgium, and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 09/2006; 116(8):2244-51. DOI: 10.1172/JCI25426
Source: PubMed


Anaphylactic shock is a sudden, life-threatening allergic reaction associated with severe hypotension. Platelet-activating factor (PAF) is implicated in the cardiovascular dysfunctions occurring in various shock syndromes, including anaphylaxis. Excessive production of the vasodilator NO causes inflammatory hypotension and shock, and it is generally accepted that transcriptionally regulated inducible iNOS is responsible for this. Nevertheless, the contribution of NO to PAF-induced shock or anaphylactic shock is still ambiguous. We studied PAF and anaphylactic shock in conscious mice. Surprisingly, hyperacute PAF shock depended entirely on NO, produced not by inducible iNOS, but by constitutive eNOS, rapidly activated via the PI3K pathway. Soluble guanylate cyclase (sGC) is generally regarded as the principal vasorelaxing mediator of NO. Nevertheless, although methylene blue partially prevented PAF shock, neither 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) nor sGCalpha1 deficiency did. Also, in 2 different models of active systemic anaphylaxis, inhibition of NOS, PI3K, or Akt or eNOS deficiency provided complete protection. In contrast to the unsubstantiated paradigm that only excessive iNOS-derived NO underlies cardiovascular collapse in shock, our data strongly support the unexpected concept that eNOS-derived NO is the principal vasodilator in anaphylactic shock and define eNOS and/or PI3K or Akt as new potential targets for treating anaphylaxis.

Download full-text


Available from: Anje Cauwels,
  • Source
    • "The effects of PAF as a bronchoconstrictor and mediator of airway hyperreactivity in bronchial asthma have long been recognized, although the use of PAF inhibitors as a therapeutic option in asthma has been ineffective (Kasperska-Zajac et al., 2008). PAF also causes severe hypotension and cardiovascular dysfunction during acute anaphylaxis, an effect that, at least in mice, is dependent on a PAF-mediated activation of eNOS and consequent NO formation (Cauwels et al., 2006). In mouse models, PAF antagonists effectively attenuated IgG-induced anaphylaxis (Jiao et al., 2014; Jonsson et al., 2011; Strait et al., 2002; Tsujimura et al., 2008) and peanut-induced anaphylaxis severity (Arias et al., 2009), but did not effectively attenuate IgEmediated anaphylaxis, which is more dependent on histamine release (Strait et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sphingosine-1phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 05/2015; DOI:10.1016/j.ejphar.2015.02.058 · 2.53 Impact Factor
  • Source
    • "It has been shown that endothelial-myocardial interactions are important in maintaining physiological regulation of cardiomyocyte [26]. ENOS is constitutively expressed in endothelium [27], and eNOS-derived NO serves as a critical endothelium-derived modulator that maintains normal function of the vasculature [28]. Recently, Thorsten et al reported that addition of endothelial to cardiomyocyte significantly increased NO production and protected cardiomyocyte from I/R injury, and endothelial dysfunction by triton X-100 incubation attenuated the recovery of cardiac function during reperfusion in Langendorff-perfused hearts subjected to I/R injury [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Extensive data have shown that exercise training can provide cardio-protection against pathological cardiac hypertrophy. However, how long the heart can retain cardio-protective phenotype after the cessation of exercise is currently unknown. In this study, we investigated the time course of the loss of cardio-protection after cessation of exercise and the signaling molecules that are responsible for the possible sustained protection. Mice were made to run on a treadmill six times a week for 4 weeks and then rested for a period of 0, 1, 2 and 4 weeks followed by isoproterenol injection for 8 days. Morphological, echocardiographic and hemodynamic changes were measured, gene reactivation was determined by real-time PCR, and the expression and phosphorylation status of several cardio-protective signaling molecules were analyzed by Western-blot. HW/BW, HW/TL and LW/BW decreased significantly in exercise training (ER) mice. The less necrosis and lower fetal gene reactivation induced by isoproterenol injection were also found in ER mice. The echocardiographic and hemodynamic changes induced by β-adrenergic overload were also attenuated in ER mice. The protective effects can be sustained for at least 2 weeks after the cessation of the training. Western-blot analysis showed that the alterations in the phosphorylation status of endothelial nitric oxide synthase (eNOS) (increase in serine 1177 and decrease in threonine 495) continued for 2 weeks after the cessation of the training whereas increases of the phosphorylation of Akt and mTOR disappeared. Further study showed that L-NG-Nitroarginine methyl ester (L-NAME) treatment abolished the cardio-protective effects of ER. Our findings demonstrate that stimulation of eNOS in mice through exercise training provides acute and sustained cardioprotection against cardiac hypertrophy.
    PLoS ONE 05/2014; 9(5):e96892. DOI:10.1371/journal.pone.0096892 · 3.23 Impact Factor
  • Source
    • "[29], [38], [40] eNOS is constitutively expressed in ECs, [41] and eNOS-derived NO serves as a pivotal endothelium-derived modulator that maintains normal function of the vasculature. [42], [43] Short episodes of myocardial I/R (ischemic preconditioning) have previously been shown to increase the release of NO from the endothelium. [22], [23] To investigate whether EC-derived NO contributes to CM protection, co-culture experiments were performed in the presence of L-NMMA, a non-specific inhibitor of NOS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial-myocardial interactions may be critically important for ischemia/reperfusion injury. Tetrahydrobiopterin (BH4) is a required cofactor for nitric oxide (NO) production by endothelial NO synthase (eNOS). Hyperglycemia (HG) leads to significant increases in oxidative stress, oxidizing BH4 to enzymatically incompetent dihydrobiopterin. How alterations in endothelial BH4 content impact myocardial ischemia/reperfusion injury remains elusive. The aim of this study was to examine the effect of endothelial-myocardial interaction on ischemia/reperfusion injury, with an emphasis on the role of endothelial BH4 content. Langendorff-perfused mouse hearts were treated by triton X-100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion. The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X-100 treated hearts compared with vehicle-treated hearts. Cardiomyocytes (CMs) were co-cultured with endothelial cells (ECs) and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation. Addition of ECs to CMs at a ratio of 1∶3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone. This EC-derived protection was abolished by HG. The addition of 100 µM sepiapterin (a BH4 precursor) or overexpression of GTP cyclohydrolase 1 (the rate-limiting enzyme for BH4 biosynthesis) in ECs by gene trasfer enhanced endothelial BH4 levels, the ratio of eNOS dimer/monomer, eNOS phosphorylation, and NO production and decreased lactate dehydrogenase activity in the presence of HG. These results demonstrate that increased BH4 content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia/reoxygenation in the presence of HG. Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia/reoxygenation injury.
    PLoS ONE 07/2013; 8(7):e70088. DOI:10.1371/journal.pone.0070088 · 3.23 Impact Factor
Show more