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

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

doi:10.1002/ajh.21582

Cited by 44 publications

(36 citation statements)

References 40 publications

(58 reference statements)

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“…In experimental animal studies, eNOS production of NO regulates expression of tissue factor, suggesting that impairment of NO production will result in elevated tissue factor and promotion of coagulation (32). In addition, NO produced by the endothelium acts locally to inhibit platelet aggregation and therefore is essential for dampening the procoagulation response (33). The differences in levels of dimethylarginines (Table 2) observed in comparisons of CKD stage 2 with stage 3 suggests impaired NO production, which therefore may exacerbate the development of a procoagulation/proinflammation state in early stage CKD and enhance its progression (34).…”

Section: Coagulation/inflammationmentioning

confidence: 99%

Plasma Metabolomic Profiles in Different Stages of CKD

Shah

Townsend

Feldman

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives CKD is a common public health problem. Identifying biomarkers adds prognostic/ diagnostic value by contributing to an understanding of CKD at the molecular level and possibly defining new drug targets. Metabolomics provides a snapshot of biochemical events at a particular time in the progression of CKD. This cross-sectional metabolomics study ascertained whether plasma metabolite profiles are significantly different in CKD stages 2, 3, and 4.Design, setting, participants, & measurements An analysis of plasma metabolites, using gas and liquid chromatography coupled to mass spectrometry, was conducted on 30 nondiabetic men ages 40-52 years, with 10 participants each in CKD stages 2, 3, and 4 based on their estimated GFR (calculated by the Modified Diet in Renal Disease formula). Participants were recruited in late 2008, and plasma samples were tested at Metabolon Inc and analyzed in 2012.Results Comparison of stage 3/stage 2 identified 62 metabolites that differed (P#0.05), with 39 higher and 23 lower in stage 3 compared with stage 2; comparisons of stage 4/stage 2 identified 111 metabolites, with 66 higher and 45 lower; and comparisons of stage 4/stage 3 identified 11 metabolites, with 7 higher and 4 lower. Major differences in metabolite profiles with increasing stage of CKD were observed, including altered arginine metabolism, elevated coagulation/inflammation, impaired carboxylate anion transport, and decreased adrenal steroid hormone production.Conclusions Global metabolite profiling of plasma uncovered potential biomarkers of stages of CKD. Moreover, these biomarkers provide insight into possible pathophysiologic processes that may contribute to progression of CKD.

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Section: Coagulation/inflammationmentioning

confidence: 99%

Plasma Metabolomic Profiles in Different Stages of CKD

Shah

Townsend

Feldman

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…9 Endothelial cell TF expression required activation of NF-B in mononuclear cells and was reduced by endothelial nitric oxide synthase or lovastatin. [9][10][11] Furthermore, it has been reported that a genetic deficiency of TF in nonhematopoietic cells reduces vascular congestion in the livers of sickle cell mice. 12 In animal models of endotoxemia, sepsis, and ischemiareperfusion injury, TF-dependent activation of coagulation enhances inflammation.…”

Section: Introductionmentioning

confidence: 99%

Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease

Chantrathammachart

Mackman

Sparkenbaugh

et al. 2012

Blood

105

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Sickle cell disease (SCD) is associated with a complex vascular pathophysiology that includes activation of coagulation and inflammation. However, the crosstalk between these 2 systems in SCD has not been investigated. Here, we examined the role of tissue factor (TF) in the activation of coagulation and inflammation in 2 different mouse models of SCD (BERK and Townes). Leukocytes isolated from BERK mice expressed TF protein and had increased TF activity compared with control mice. We found that an inhibitory anti-TF antibody abrogated the activation of coagulation but had no effect on hemolysis or anemia. Importantly, inhibition of TF also attenuated inflammation and endothelial cell injury as demonstrated by reduced plasma levels of IL-6, serum amyloid P, and soluble vascular cell adhesion molecule-1. In addition, we found decreased levels of the chemokines MCP-1 and KC, as well as myeloperoxidase in the lungs of sickle cell mice treated with the anti-TF antibody. Finally, we found that endothelial cell-specific deletion of TF had no effect on coagulation but selectively attenuated plasma levels of IL-6. Our data indicate that different cellular sources of TF contribute to activation of coagulation, vascular inflammation, and endothelial cell injury. Furthermore, it appears that TF contributes to these processes without affecting intravascular hemolysis. (Blood. 2012;120(3):636-646)

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“…Some studies have indicated that TMPRSS6 polymorphisms directly affect hepcidin transcription, while others have suggested that the polymorphisms may addictionally influence iron homeostasis by mechanisms independent of hepcidin expression. The latter theory could explain why rs855791 has not been found to be significantly associated with serum hepcidin in some studies [3].…”

Section: Dasatinib Therapy Can Results In Significant Pulmonary Toxicitymentioning

confidence: 99%

“…TMPRSS6 polymorphisms have been implicated in iron metabolism in both animal and human studies. The common rs855791 polymorphism (NM_153609.3:c.2207C>T) causes a nonsynonymous valine to alanine change (p.V736A), and the T allele (encoding valine) has been associated with lower hemoglobin and ferritin concentrations as well as increased serum transferrin receptor and transferrin concentrations in all populations [3]. Moreover, this polymorphism influences iron overload in hereditary hemochromatosis as well as the development of nonalcoholic fatty liver disease [4,5] and it has been associated with iron deficiency anemia in women of reproductive ages [6].…”

Section: Dasatinib Therapy Can Results In Significant Pulmonary Toxicitymentioning

confidence: 99%

Dasatinib therapy can result in significant pulmonary toxicity

et al. 2015

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thromboembolism (VTE) in SCD, with a higher mortality observed in patients with VTE compared to those without this complication [5].There are few studies specifically addressing treatment of PHT in SCD. Current strategies include optimizing SCD therapy and identifying potentially modifiable etiologies such as obstructive sleep apnea, pulmonary thrombosis, and left ventricular dysfunction. Hydroxyurea, approved for treatment of severe anemia and frequent vaso-occlusive episodes, has the potential benefit of being an NO donor. Endothelin receptor antagonists and prostaglandin therapy are approved for treatment of pulmonary arterial hypertension and have been recommended for select SCD patients with marked elevation of pulmonary vascular resistance and normal pulmonary artery occlusion pressure on RHC, and related symptoms [1]. Phosphodiesterase-5 inhibitor therapy is presently not recommended as first-line treatment for RHC-confirmed PHT due to the association of sildenafil with increased hospitalizations for pain crises. Riociguat, a soluble guanylate cyclase stimulator, is a vasodilator that bypasses the NO pathway. It has shown promise in CTEPH and PAH, but has not yet been studied in SCD. Although a study of the low molecular weight heparin, tinzaparin showed a reduction in the duration of pain crisis and hospitalization [6], most studies of anticoagulants in SCD have been small and poorly controlled. Treatment with the factor Xa inhibitor, rivaroxaban, as well as PAR-2 or IL-6 deficiency have been reported to attenuate PHT in animal models [7]. A study of rivaroxaban in SCD is ongoing to assess its pharmacodynamics effects (www.clinical trials.gov. identifier NCT02072668). Finally, pulmonary endarterectomy is standard for non-SCD patients with CTEPH, but the experience in SCD is limited, possibly due to concerns for a high risk of perioperative complications. Pulmonary endarterectomy requires cardiopulmonary bypass, hypothermia, and periods of circulatory arrest, which will likely increase the risk of sickling. These two cases, along with the previously published reports of four patients who underwent pulmonary endarterectomy [8][9][10], demonstrate that patients can undergo this procedure safely, with symptomatic and hemodynamic benefit. In summary, SCD patients with CTEPH, should be considered for pulmonary endarterectomy. AcknowledgmentAuthors thank Ertan Pamuklar, MD for help with the figure.

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

Cited by 44 publications

References 40 publications

Plasma Metabolomic Profiles in Different Stages of CKD

Plasma Metabolomic Profiles in Different Stages of CKD

Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease

Dasatinib therapy can result in significant pulmonary toxicity

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