title: Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease.
abstract: Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation, dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.
authors.affiliation: Cardiovascular Research Center Lariboisière, INSERM U689, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sabaa
authors.forename: Lucia
authors.initials: L
authors.lastname: de Franceschi
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.forename: Yves
authors.initials: Y
authors.lastname: Castier
authors.forename: Giorgio
authors.initials: G
authors.lastname: Malpeli
authors.forename: Haythem
authors.initials: H
authors.lastname: Debbabi
authors.forename: Ariane
authors.initials: A
authors.lastname: Galaup
authors.forename: Micheline
authors.initials: M
authors.lastname: Maier-Redelsperger
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.forename: Bernard
authors.initials: B
authors.lastname: Levy
authors.forename: Robert
authors.initials: R
authors.lastname: Girot
authors.forename: Yves
authors.initials: Y
authors.lastname: Beuzard
authors.forename: Christophe
authors.initials: C
authors.lastname: Leboeuf
authors.forename: Annie
authors.initials: A
authors.lastname: Henri
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
mesh_terms: D000755:Anemia, Sickle Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D000860:Hypoxia; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow; D012079:Renal Circulation / Q000502:physiology; D013449:Sulfonamides / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan