Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Sabaa, Nathalie; Franceschi, Lucia De; Bonnin, Philippe; Castier, Yves; Malpeli, Giorgio; Debbabi, Haythem; Galaup, Ariane; Maïer-Redelsperger, Micheline; Vandermeersch, Sophie; Scarpa, Aldo; Janin, Anne; Lévy, Bernard; Girot, Robert; Beuzard, Yves; Lebœuf, Christophe; Henri, A; Germain, Stéphane; Dussaule, Jean–Claude; Tharaux, Pierre‐Louis

doi:10.1172/jci33308

Cited by 124 publications

(136 citation statements)

References 54 publications

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“…This is also correct. Published data evidence the involvement of oxidative stress (79,100,105,108,113,115,116,121,123,132,134,135), inflammation (9, 22, 27, 32, 101, 105-108, 115, 124-127, 134), dyslipidemia (135)(136)(137)(138), microparticles (89,122,123,139), and vasoactive peptides (110,111,(140)(141)(142)(143). These additional pathways (depicted in Figure 2) are potentially additive or synergistic to intravascular hemolysis-like mechanisms.…”

Section: Controversies Regarding the Hyperhemolysis Modelmentioning

confidence: 99%

Intravascular hemolysis and the pathophysiology of sickle cell disease

Kato¹,

Steinberg²,

Gladwin³

2017

Journal of Clinical Investigation

521

444

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Section: Controversies Regarding the Hyperhemolysis Modelmentioning

confidence: 99%

Intravascular hemolysis and the pathophysiology of sickle cell disease

Kato¹,

Steinberg²,

Gladwin³

2017

Journal of Clinical Investigation

521

444

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“…In addition, the abnormally activated ET-1 system and the reduced NO bioavaibility associated with activated endothelial vascular cells, highly adherent neutrophils and dense, dehydrated sickle red cells, all participate in sickle cell-related tissue injury. 4,16,17 Although the liver is not one of the main target organs of SCD, its anatomic organization and function, characterized by a sluggish circulation, high metabolic rate and complex regulation of blood flow in the microcirculation, make this an interesting "window organ" to study the pathogenesis of sickle cell-related tissue damage.…”

Section: Introductionmentioning

confidence: 99%

Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy

Siciliano¹,

Malpeli²,

Platt³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundSickle cell disease, a genetic red cell disorder inherited in an autosomal recessive manner, occurs throughout the world. Hepatic dysfunction and liver damage may be present in sickle cell disease, but the pathogenesis of these conditions is only partially understood. Design and MethodsTransgenic mice with sickle cell disease (SAD mice) and wild-type mice were exposed to an ischemic/reperfusion stress. The following parameters were evaluated: hematologic profile, transaminase and bilirubin levels, liver histopathology, and mRNA levels of nuclear factor-κB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heme oxygenase-1 and phosphodiesterase-1, -2, -3, and -4 genes in hepatocytes obtained by laser-capture microdissection. Immunoblotting was used to analyze the expression of the following proteins: nuclear factor-κB p65 and phospho-nuclear factor-κB p65, heme oxygenase-1, biliverdin reductase, heat shock protein-70, heat shock protein-27 and peroxiredoxin-6. A subgroup of SAD mice was treated with the phosphodiesterase-4 inhibitor rolipram (30 mg/Kg/day by gavage) during the ischemic/reperfusion protocol. ResultsIn SAD mice the ischemic/reperfusion stress induced liver damage compatible with sickle cell disease hepatopathy, which was associated with: (i) lack of hypoxia-induced nuclear factor-κB p65 activation; (ii) imbalance in the endothelial/inducible nitric oxide synthase response to ischemic/reperfusion stress; (iii) lack of hypoxia-induced increased expression of heme oxygenase-1/biliverdin reductase paralleled by a compensatory increased expression of heat shock proteins 70 and 27 and peroxiredoxin-6; and (iv) up-regulation of the phosphodiesterase-1, -2, -3, and -4 genes. In SAD mice the phosphodiesterase-4 inhibitor rolipram attenuated the ischemic/reperfusion-related microcirculatory dysfunction, reduced the inflammatory cell infiltration and induced the heme oxygenase-1/ biliverdin reductase cytoprotective systems. ConclusionsIn SAD mice, sickle cell hepatopathy is associated with perturbed nuclear factor-κB p65 signaling with an imbalance of endothelial/inducible nitric oxide synthase levels, lack of heme oxygenase-1/biliverdin reductase expression and up-regulation of two novel cytoprotective systems: heat shock protein-27 and peroxiredoxin-6.Key words: NF-κB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heat shock protein-70, heat shock protein-27, peroxiredoxin-6.

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“…17 By competing with RBC membrane-associated ICAM-4 for binding to endothelial aVβ3 integrins, soluble ICAM-4 might reduce red cell/endothelium interactions thereby moderating an otherwise exaggerated adhesiveness of SS RBC to the vascular wall. The reduced level of CD36 on SAD RBC could result from the high plasma level of endothelin-1 found in both SS patients and SAD mice, 34,35 which decreases CD36 protein expression, an effect recently reported for vascular smooth muscle cells. 36 In conclusion, the present work shows an over-adhesiveness to endothelium of SAD mouse RBC, with this phenomenon depending on two adhesion proteins, ICAM-4 and CD36, as previously reported for human SS RBC.…”

Section: Discussionmentioning

confidence: 71%

Intercellular adhesion molecule-4 and CD36 are implicated in the abnormal adhesiveness of sickle cell SAD mouse erythrocytes to endothelium

Trinh–Trang–Tan¹,

Vilela-Lamego²,

Picot³

et al. 2009

Haematologica

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BackgroundAbnormal adhesiveness of red blood cells to endothelium has been implicated in vaso-occlusive crisis of sickle cell disease. The present study examined whether the SAD mouse model exhibits the same abnormalities of red blood cell adhesion as those found in human sickle cell disease. Design and MethodsThe repertoire of adhesive molecules on murine erythrocytes and bEnd.3 microvascular endothelial cells was determined by flow cytometry using monoclonal antibodies or by western blotting. Adhesion was investigated in dynamic conditions and measured at different shear stresses. ResultsCD36, CD47 and intercellular adhesion molecular-4, but not Lutheran blood group antigen/basal cell adhesion molecule, are present on mouse mature erythrocytes. a4β1 are not expressed on SAD and wild type reticulocytes. Endothelial bEnd.3 cells express aVβ3, a4β1, CD47, vascular cell adhesion molecule-1, and Lutheran blood group antigen/basal cell adhesion molecule, but not CD36. Adhesion of SAD red cells is: (i) 2-to 3-fold higher than that of wild type red cells; (ii) further increased on platelet activating factor-activated endothelium; (iii) not stimulated by epinephrine; (iv) inhibited after treating the endothelium with a peptide reproducing one of the binding sequences of mouse intercellular adhesion molecular-4, or with monoclonal antibody against murine av integrin; and (v) inhibited after pretreatment of red blood cells with anti-mouse CD36 monoclonal antibodies. The combination of treatments with intercellular adhesion molecular-4 peptide and anti-CD36 monoclonal antibodies eliminates excess adhesion of SAD red cells. The phosphorylation state of intercellular adhesion molecular-4 and CD36 is probably not involved in the over-adhesiveness of SAD erythrocytes. ConclusionsIntercellular adhesion molecular-4/avβ3 and CD36/thrombospondin interactions might contribute to the abnormally high adhesiveness of SAD red cells. The SAD mouse is a valuable animal model for investigating adhesion processes of sickle cell disease. Haematologica 2010;95:730-737. doi:10.3324/haematol.2009 Intercellular adhesion molecule-4 and CD36 are implicated in the abnormal adhesiveness of sickle cell SAD mouse erythrocytes to endothelium © F e r r a t a S t o r t i F o u n d a t i o n

show abstract

Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Cited by 124 publications

References 54 publications

Intravascular hemolysis and the pathophysiology of sickle cell disease

Intravascular hemolysis and the pathophysiology of sickle cell disease

Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy

Intercellular adhesion molecule-4 and CD36 are implicated in the abnormal adhesiveness of sickle cell SAD mouse erythrocytes to endothelium

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