Nuclear factor-kappa B (NFκB) component p50 in blood mononuclear cells regulates endothelial tissue factor expression in sickle transgenic mice: implications for the coagulopathy of sickle cell disease

Kollander, Rahn; Solovey, Anna; Milbauer, Liming; Abdulla, Fuad; Kelm, Robert J.; Hebbel, Robert P.

doi:10.1016/j.trsl.2009.10.004

Cited by 40 publications

(50 citation statements)

References 32 publications

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“…Thus, the relevant effect of H/R on triggering TF expression is exerted early after cessation of hypoxia, in the first few hours of the reoxygenation period, consistent with our previous observations of many other parameters post-H/R [4,5,6], even though maximal expression of actual TF protein requires many hours longer [3]. These results suggest not only that NO may be of therapeutic benefit but also that endogenous NO could be a regulator of TF expression, as influenced by inflammation.…”

Section: Modulation By Inhaled Nosupporting

confidence: 90%

“…Elsewhere, we have unambiguously demonstrated that this TF expression mouse is triggered by the inflammatory state that is known to develop in the NY1DD mouse on exposure to H/R [6]. We believe that the documented presence of an inflammatory state in the hBERK1 mouse [8] also possibly accounts for its TF expression even at ambient air, although this has not been unambiguously proven.…”

Section: Discussionmentioning

confidence: 80%

“…Thus, it shows efficacy only if it is present during the initial triggering of TF expression [4,6]. This observation has direct implications for potential clinical application of inhaled NO therapy.…”

Section: Discussionmentioning

confidence: 99%

“…New studies presented elsewhere have established that the mechanism underlying stimulation of endothelial TF expression in the post-H/R NY1DD sickle mouse is strictly dependent on NFjB(p50) within blood mononuclear cells, a feature of the ischemia/reperfusion-induced inflammatory state [6]. This observation is relevant because human and murine sickle states are both characterized by this state [7,8].…”

Section: Introductionmentioning

confidence: 98%

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Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

et al. 2009

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Activation of the coagulation system is a characteristic feature of sickle cell anemia, which also includes clinical thrombosis. The sickle transgenic mouse abnormally expresses tissue factor (TF) on the pulmonary vein endothelium. Knowing that this aberrancy is stimulated by inflammation, we sought to determine whether nitric oxide (NO) contributes to regulation of endothelial TF expression in the sickle mouse model. We used the NY1DD sickle mouse, which exhibits a low-TF to high-TF phenotype switch on exposure to hypoxia/reoxygenation. Manipulations of NO biology, such as breathing NO or addition of arginine or L-NAME (N-nitro-L-arginine-methyl-ester) to the diet, caused significant modulations of TF expression. This was also seen in hBERK1 sickle mice, which have a different genetic background and already have high-TF even at ambient air. Study of NY1DD animals bred to overexpress endothelial nitric oxide synthase (eNOS; eNOSTg) or to have an eNOS knockout state (one eNOS 2/2 animal and several eNOS 1/2 animals) demonstrated that eNOS modulates endothelial TF expression in vivo by down-regulating it. Thus, the biodeficiency of NO characteristic of patients with sickle cell anemia may heighten risk for activation of the coagulation system. Am. J. Hematol. 85:41-45, 2010. V

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Section: Modulation By Inhaled Nosupporting

confidence: 90%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

et al. 2009

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“…Previous work has also shown the role of NF-kB signaling in blood mononuclear cells in regulating endothelial tissue factor expression in sickle transgenic mice with implications for the coagulopathy of SCD. 41 The current data further emphasize the association of pathways such as inflammation, T-cell signaling, and coagulation in the development of SCD complications from HgS polymerization. Patients in cluster 1 demonstrated a greater propensity toward a more severe clinical profile as evidenced by a higher WBC count, a trend toward more severe hemolytic anemia, and history of ACS, all of which are markers of poor outcomes in SCD.…”

Section: Training Cohort Testing Cohort West African Children Cohortmentioning

confidence: 57%

Association of circulating transcriptomic profiles with mortality in sickle cell disease

Desai

Lei

Bahroos

et al. 2017

Blood

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• We validated the association of a circulating genome-wide gene expression profile with poor outcomes in 3 cohorts of SCD.• A composite risk score using this genomic biomarker with clinical risk factors exhibited improved prediction than clinical factors alone.Sickle cell disease (SCD) complications are associated with increased morbidity and risk of mortality. We sought to identify a circulating transcriptomic profile predictive of these poor outcomes in SCD. Training and testing cohorts consisting of adult patients with SCD were recruited and prospectively followed. A pathway-based signature derived from grouping peripheral blood mononuclear cell transcriptomes distinguished 2 patient clusters with differences in survival in the training cohort. These findings were validated in a testing cohort in which the association between cluster 1 molecular profiling and mortality remained significant in a fully adjusted model. In a third cohort of West African children with SCD, cluster 1 differentiated SCD severity using a published scoring index. Finally, a risk score composed of assigning weights to cluster 1 profiling, along with established clinical risk factors using tricuspid regurgitation velocity, white blood cell count, history of acute chest syndrome, and hemoglobin levels, demonstrated a higher hazard ratio for mortality in both the training and testing cohorts compared with clinical risk factors or cluster 1 data alone. Circulating transcriptomic profiles are a powerful method to risk-stratify severity of disease and poor outcomes in both children and adults, respectively, with SCD and highlight potential associated molecular pathways. (Blood. 2017;129(22):3009-3016)

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A monocyte‐TNF‐endothelial activation axis in sickle transgenic mice: Therapeutic benefit from TNF blockade

et al. 2017

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Elaboration of tumor necrosis factor (TNF) is a very early event in development of ischemia/reperfusion injury pathophysiology. Therefore, TNF may be a prominent mediator of endothelial cell and vascular wall dysfunction in sickle cell anemia, a hypothesis we addressed using NY1DD, S+SAntilles, and SS‐BERK sickle transgenic mice. Transfusion experiments revealed participation of abnormally activated blood monocytes exerting an endothelial activating effect, dependent upon Egr‐1 in both vessel wall and blood cells, and upon NFκB(p50) in a blood cell only. Involvement of TNF was identified by beneficial impact from TNF blockers, etanercept and infliximab, with less benefit from an IL‐1 blocker, anakinra. In therapeutic studies, etanercept ameliorated multiple disturbances of the murine sickle condition: monocyte activation, blood biomarkers of inflammation, low platelet count and Hb, vascular stasis triggered by hypoxia/reoxygenation (but not if triggered by hemin infusion), tissue production of neuro‐inflammatory mediators, endothelial activation (monitored by tissue factor and VCAM‐1 expression), histopathologic liver injury, and three surrogate markers of pulmonary hypertension (perivascular inflammatory aggregates, arteriolar muscularization, and right ventricular mean systolic pressure). In aggregate, these studies identify a prominent—and possibly dominant—role for an abnormal monocyte‐TNF‐endothelial activation axis in the sickle context. Its presence, plus the many benefits of etanercept observed here, argue that pilot testing of TNF blockade should be considered for human sickle cell anemia, a challenging but achievable translational research goal.

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Nuclear factor-kappa B (NFκB) component p50 in blood mononuclear cells regulates endothelial tissue factor expression in sickle transgenic mice: implications for the coagulopathy of sickle cell disease

Cited by 40 publications

References 32 publications

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

Association of circulating transcriptomic profiles with mortality in sickle cell disease

A monocyte‐TNF‐endothelial activation axis in sickle transgenic mice: Therapeutic benefit from TNF blockade

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