Extracellular histones disarrange vasoactive mediators release through a <scp>COX</scp>‐<scp>NOS</scp> interaction in human endothelial cells

Pérez‐Cremades, Daniel; Bueno-Betí, Carlos; García-Giménez, José Luis; Ibáñez-Cabellos, José Santiago; Hermenegildo, Carlos; Pallardó, Federico V.; Novella, Susana

doi:10.1111/jcmm.13088

Cited by 32 publications

(35 citation statements)

References 53 publications

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“…Extracellular histones have been found to stimulate calcium entry in multiple cell types [15,24], to stimulate cytokine synthesis/release [14,25,26,27,28,29] and to inhibit macrophage phagocytosis [30]. Histone injections in mice increased circulating cytokines [21].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Histones Activate Plasma Membrane Toll-Like Receptor 9 to Trigger Calcium Oscillations in Rat Pancreatic Acinar Tumor Cell AR4-2J

Guo

Cui

2018

Cells

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In acute pancreatitis, histones are released by infiltrating neutrophils, but how histones modulate pancreatic acinar cell function has not been investigated. We have examined histone modulation of rat pancreatic acini and pancreatic acinar tumor cell AR4-2J by calcium imaging. Histones were found to have no effect on calcium in pancreatic acini but blocked calcium oscillations induced by cholecystokinin or acetylcholine. Both mixed (Hx) and individual (H1, H2A, H2B, H3, H4) histones induced calcium oscillations in AR4-2J. RT-PCR and Western blot verified the expression of histone-targeted Toll-like receptor (TLR) 2, 4 and 9. Immunocytochemistry identified TLR2/TLR4 on apical plasma membrane and TLR9 in zymogen granule regions in pancreatic acini. TLR2 was found on neighboring and TLR9 on peripheral plasma membranes, but TLR4 was in the nucleus in AR4-2J clusters. Neither TLR2 agonist zymosan-A nor TLR4 agonist lipopolysaccharide had any effect on calcium, but TLR9 agonist ODN1826 induced calcium oscillations; TLR9 antagonist ODN2088 blocked H4-induced calcium oscillations in AR4-2J, which also disappeared after treatment of AR4-2J with glucocorticoid dexamethasone, with concurrent TLR9 migration from plasma membrane to cell interiors. TLR9 down regulation with siRNA suppressed H4-induced calcium oscillations. These data together suggest that extracellular histones activate plasma membrane TLR9 to trigger calcium oscillations in AR4-2J cells.

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Section: Introductionmentioning

confidence: 99%

Extracellular Histones Activate Plasma Membrane Toll-Like Receptor 9 to Trigger Calcium Oscillations in Rat Pancreatic Acinar Tumor Cell AR4-2J

Guo

Cui

2018

Cells

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“…Histones also interact with Toll-like receptors (TLRs) and proin ammatory cytokine/chemokine, released through MyD88, NFκB, and NLRP3 in ammasomedependent pathways [17,21]. In previous studies, extracellular histone-treated HUVECs decreased eNOS expression [39], suppressed the Akt signaling pathway [15], and eventually induced apoptosis in a dosedependent manner. In many sepsis animal models, endothelial cell damage is associated with apoptosis [19,40,41].…”

Section: Discussionmentioning

confidence: 97%

Exosomes from Adipose Tissue-Derived Mesenchymal Stem Cells Ameliorate Histone-Induced Acute Lung Injury by Activating the PI3K/Akt Pathway in Endothelial Cells.

Mizuta

Akahoshi

Guo

et al. 2020

Preprint

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BackgroundMesenchymal stem cells (MSCs), including adipose-derived mesenchymal stem cells (ADSCs), have been shown to attenuate organ damage in acute respiratory distress syndrome (ARDS) and sepsis; however, the underlying mechanisms have not been fully understood. In this study, we aimed to explore the potential roles and molecular mechanisms of action of ADSCs in histone-induced endothelial damage. MethodsMale C57BL/6N mice were intravenously injected with ADSCs, followed by histones or a vehicle. The mice in each group were assessed for survival, pulmonary vascular permeability, and histological changes. A co-culture model with primary human umbilical vein endothelial cells (HUVECs) exposed to histones was used to clarify the paracrine effect of ADSCs. Overexpression and inhibition of miR-126 ADSCs were also examined as causative factors for endothelial protection.ResultsThe administration of ADSCs markedly improved survival, inhibited histone-mediated lung hemorrhage and edema, and attenuated vascular hyper-permeability in mice. ADSCs were engrafted in the injured lung and attenuated histone-induced endothelial cell apoptosis. ADSCs showed endothelial protection (via a paracrine effect) and Akt phosphorylation in the histone-exposed HUVECs. Notably, increased Akt phosphorylation by ADSCs was mostly mediated by exosomes in histone-induced cytotoxicity and lung damage. Moreover, inhibition of miR-126, which is known to be present in exosomes, in ADSCs did not increase Akt phosphorylation in histone-exposed HUVECs. ConclusionADSC-derived exosomes may exert protective effects on endothelial cells via activation of the PI3K/Akt pathway.

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“…People who smoke also have disorders related to the cyclooxygenase (COX) pathway, which might be involved in NO homeostasis disturbances [50,51]. An in vitro study shown that an increase in intracellular O 2 levels observed in histone-treated HUVEC, at least in part produced by COX-2 activity, contributes to decreased eNOS expression and NO bioavailability [52].…”

Section: Discussionmentioning

confidence: 99%

Influence of Active Exposure to Tobacco Smoke on Nitric Oxide Status of Pregnant Women

Chełchowska¹,

Ambroszkiewicz²,

Gajewska³

et al. 2018

IJERPH

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Smoking tobacco can impair proper vascular endothelial functioning. This is exhibited through reduced nitric oxide synthesis as well as activity due to accompanying oxidative stress. We examined the relationship between nitric oxide and markers of oxidative stress/antioxidant defense in serum of smoking and non-smoking pregnant women. Subjects included 99 healthy pregnant women, who were tested for nitric oxide (NO), endothelial (eNOS) and inducible (iNOS) nitric oxide synthase, total oxidant capacity (TOC), and total antioxidant capacity (TAC). NO, eNOS, and TAC serum concentrations were significantly lower (p < 0.005), but iNOS (p < 0.05) and TOC (p < 0.001) were higher in smokers than in non-smokers. Multivariate regression analysis showed associations between NO concentration and eNOS, TAC, and smoking status in the whole group of patients. In the model estimated separately for smokers, the highest impact of eNOS (β = 0.375; p = 0.021) and cotinine (β = −0.323; p = 0.037) was indicated for NO concentration. In the model of non-smokers, eNOS (β = 0.291, p = 0.030) and TAC (β = 0.350; p = 0.015) were important for NO level. Smoking during pregnancy could exacerbate oxidative stress, impair the action of nitric oxide synthases, and adversely affect the balance of oxygen and nitrogen metabolism. Relationships between NO concentrations and TAC in the studied women’s blood can confirm the antioxidant nature of nitric oxide.

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Extracellular histones disarrange vasoactive mediators release through a COX‐NOS interaction in human endothelial cells

Cited by 32 publications

References 53 publications

Extracellular Histones Activate Plasma Membrane Toll-Like Receptor 9 to Trigger Calcium Oscillations in Rat Pancreatic Acinar Tumor Cell AR4-2J

Extracellular Histones Activate Plasma Membrane Toll-Like Receptor 9 to Trigger Calcium Oscillations in Rat Pancreatic Acinar Tumor Cell AR4-2J

Exosomes from Adipose Tissue-Derived Mesenchymal Stem Cells Ameliorate Histone-Induced Acute Lung Injury by Activating the PI3K/Akt Pathway in Endothelial Cells.

Influence of Active Exposure to Tobacco Smoke on Nitric Oxide Status of Pregnant Women

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