Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2+ influx

Lantoine, Frédérique; Iouzalen, Lahcen; Devynck, Marie‐Aude; Brussel, Elisabeth Millanvoye-Van; David‐Dufilho, Monique

doi:10.1042/bj3300695

Cited by 117 publications

(96 citation statements)

References 38 publications

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“…Ca 2+ release from intracellular stores was required for the activation of eNOS by flow and agonists in aorta [31]. Other studies have found that sustained eNOS activation in endothelial cells by agonists required capacitative Ca 2+ entry [41,42]. Our data also show that sustained eNOS activation by bradykinin is dependent on Ca 2+ entry (Fig.…”

Section: Discussionsupporting

confidence: 74%

Chronic exposure to high glucose impairs bradykinin-stimulated nitric oxide production by interfering with the phospholipase-C-implicated signalling pathway in endothelial cells: evidence for the involvement of protein kinase C

Tang

2004

Diabetologia

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Aims/hypothesis. Overwhelming evidence indicates that endothelial cell dysfunction in diabetes is characterised by diminished endothelium-dependent relaxation, but the matter of the underlying molecular mechanism remains unclear. As nitric oxide (NO) production from the endothelium is the major player in endothelium-mediated vascular relaxation, we investigated the effects of high glucose on NO production, and the possible alterations of signalling pathways implicated in this scenario. Methods. NO production and intracellular Ca 2+ levels ([Ca 2+ ] i ) were assessed using the fluorescent probes 4,5-diaminofluorescein diacetate and fura-2 respectively. Results. Exposure of cultured bovine aortic endothelial cells to high glucose for 5 or 10 days significantly reduced NO production induced by bradykinin (but not by Ca 2+ ionophore) in a time-and dose-dependent manner. This was probably due to an attenuation in bradykinin-induced elevations of [Ca 2+ ] i under these conditions, since a close correlation between [Ca 2+ ] i increases and NO generation was observed in intact bovine aortic endothelial cells. Both bradykinin-promoted intracellular Ca 2+ mobilisation and extracellular Ca 2+ entry were affected. Moreover, bradykinin-induced formation of Ins(1,4,5)P 3 , a phospholipase C product leading to increases in [Ca 2+ ] i , was also inhibited following high glucose culture. This abnormality was not attributable to a decrease in inositol phospholipids, but possibly to a reduction in the number of bradykinin receptors. The alterations in NO production, the increases in [Ca 2+ ] i , and the bradykinin receptor number due to high glucose could be largely reversed by protein kinase C inhibitors and D-α-tocopherol (antioxidant). Conclusions/interpretation. Chronic exposure to high glucose reduces NO generation in endothelial cells, probably by impairing phospholipase-C-mediated Ca 2+ signalling due to excess protein kinase C activation. This defect in NO release may contribute to the diminished endothelium-dependent relaxation and thus to the development of cardiovascular diseases in diabetes.

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Section: Discussionsupporting

confidence: 74%

Chronic exposure to high glucose impairs bradykinin-stimulated nitric oxide production by interfering with the phospholipase-C-implicated signalling pathway in endothelial cells: evidence for the involvement of protein kinase C

Tang

2004

Diabetologia

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“…Increases in intracellular free Ca 2ϩ , [Ca 2ϩ ] i , in response to histamine, have been demonstrated for EA.hy 926 cells, 22 as well as HUVECs. 8 In human endothelial cells, the Ca 2ϩ -sensitive target responsible for the histamine-induced eNOS expression seems to be CaMK II, a ubiquitous enzyme that is also present in vascular endothelial cells. 23 The histamine-induced eNOS expression was completely abolished by KN-93, a specific inhibitor of CaMK II ( Figure 4A), whereas the inactive analog of KN-93, KN-92, was without effect ( Figure 4A).…”

Section: Discussionmentioning

confidence: 99%

“…7 By occupying H 1 receptors on endothelial cells, histamine activates endothelial nitric oxide synthase (eNOS). 8 The nitric oxide (NO) produced by eNOS dilates all kinds of blood vessels, including human coronary arteries, 9 and has protective effects against platelet and leukocyte adhesion and smooth muscle proliferation and, thus, probably atherosclerosis. 10 However, the direct activation of eNOS by histamine represents a short-term and probably transient action of the amine.…”

mentioning

confidence: 99%

Histamine Upregulates Gene Expression of Endothelial Nitric Oxide Synthase in Human Vascular Endothelial Cells

Burkhardt

Heinrich

et al. 2003

Circulation

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Background-Histamine has a short-term, transient, stimulating effect on endothelial nitric oxide synthase (eNOS) activity; however, long-term effects on eNOS have not been described yet. In addition, the vascular effect of histamine seems to depend critically on eNOS functionality. Therefore, we studied the effects of histamine on eNOS gene expression and function. Methods and Results-In human umbilical vein endothelial cells (HUVECs) and HUVEC-derived EA.hy 926 cells, histamine upregulated eNOS mRNA (RNase protection assay) and protein (electron microscopic immunocytochemistry) expression. The upregulation of eNOS could be prevented by mepyramine, a selective antagonist at the H 1 receptor, but not by H 2 and H 3 receptor antagonists. Incubation of EA.hy 926 cells with histamine led to the activation of calcium/calmodulin-dependent protein kinase II (CaMK II; in vitro phosphorylation assay). The histamine-induced eNOS expression was completely prevented by KN-93, an inhibitor of CaMK II. Histamine increased the activity of a 1.6-kb human eNOS promoter fragment (luciferase reporter gene assay), an effect that was also blocked by mepyramine. Under normal conditions, eNOS upregulation by histamine resulted in increased nitric oxide production (measured by nitric oxide chemiluminescence and RFL-6 reporter cell assay). Under conditions of oxidative stress, however, the eNOS upregulated by histamine produced reactive oxygen species (CM-H 2 DCFDA oxidation-based fluorescence assay). Conclusions-Stimulation of the H 1 receptor increases eNOS transcription in endothelial cells by a signaling pathway involving CaMK II. This eNOS upregulation may be protective under normal conditions, but it may become harmful under conditions of oxidative stress when eNOS produces reactive oxygen species at the expense of nitric oxide.

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“…Vasoactive agents such as Bk and ATP are known to increase the generation of NO released by endothelial NOS (16)(17)(18). Administration of Bk (1 M) to control cells when the concentration of oxygen was 80 and 40 M gave rise to a transient generation of NO that reached a peak concentration of 0.76 Ϯ 0.09 M (n ϭ 5) and was similar at both concentrations of oxygen (Fig.…”

mentioning

confidence: 99%

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

Clementi

Brown

Foxwell

et al. 1999

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

271

200

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Two enzymes, soluble guanylyl cyclase and cytochrome c oxidase, have been shown to be exquisitely sensitive to nitric oxide (NO) at low physiological concentrations. Activation of the soluble guanylyl cyclase by endogenous NO and the consequent increase in the second messenger cyclic GMP are now known to control a variety of biological functions. Cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, is inhibited by NO. However, it is not clear whether NO produced by the constitutive NO synthase interacts with cytochrome c oxidase, nor is it known what the biological consequences of such an interaction might be. We now show that NO generated by vascular endothelial cells under basal and stimulated conditions modulates the respiration of these cells in response to acute changes in oxygen concentration. This action occurs at the cytochrome c oxidase and depends on inf lux of calcium. Thus, NO plays a physiological role in adjusting the capacity of this enzyme to use oxygen, allowing endothelial cells to adapt to acute changes in their environment.Evidence in favor of a role of endogenous nitric oxide (NO) as a modulator of cell respiration has been derived from experiments in cells activated with cytokines and bacterial products in which NO is generated continuously in large quantities by the inducible NO synthase (NOS). In these conditions, NOinduced inhibition of cell respiration is persistent and attributable to nonselective inhibition of various mitochondrial enzymes, including complexes I-IV in the respiratory chain. Such inhibition contributes to the pathological actions of NO (1). On the other hand, experiments in animals have suggested that inhibition of endogenous generation of NO increases whole body oxygen consumption (2, 3), and bradykinin (Bk) and carbachol have been shown to reduce oxygen consumption in skeletal and cardiac muscle in a manner that could be prevented by an inhibitor of NOS (3-5).Exogenous administration of low concentrations of NO inhibits cytochrome c oxidase (complex IV in the mitochondrial respiratory chain) in a variety of cells and isolated mitochondria. Such inhibition is competitive with oxygen and is fully reversible (6-9) even after several hours (10). These findings suggest that endogenous NO may regulate cell respiration. To test this hypothesis, we have analyzed the effect of endogenous NO, generated under basal conditions and after stimulation with Bk and ATP, on respiration in porcine aortic endothelial cells. Our results show that endogenously released NO, by acting on cytochrome c oxidase, is responsible for the physiological regulation of respiration in these cells. MATERIALS AND METHODSMaterials. Culture media and fetal calf serum were from GIBCO. Fura-2 acetoxymethylester was from Calbiochem. Other reagents were from Sigma.Cell Culture and Preparation. Endothelial cells were prepared from fresh porcine thoracic aortae obtained from the abattoir, were cultured overnight in DMEM 20% fetal calf serum, and then were grown to confluence...

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Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2+ influx

Cited by 117 publications

References 38 publications

Chronic exposure to high glucose impairs bradykinin-stimulated nitric oxide production by interfering with the phospholipase-C-implicated signalling pathway in endothelial cells: evidence for the involvement of protein kinase C

Chronic exposure to high glucose impairs bradykinin-stimulated nitric oxide production by interfering with the phospholipase-C-implicated signalling pathway in endothelial cells: evidence for the involvement of protein kinase C

Histamine Upregulates Gene Expression of Endothelial Nitric Oxide Synthase in Human Vascular Endothelial Cells

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

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