Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease.
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.
Sabaa
Nathalie
N
Cardiovascular Research Center Lariboisière, INSERM U689, Paris, France.
de Franceschi
Lucia
L
Bonnin
Philippe
P
Castier
Yves
Y
Malpeli
Giorgio
G
Debbabi
Haythem
H
Galaup
Ariane
A
Maier-Redelsperger
Micheline
M
Vandermeersch
Sophie
S
Scarpa
Aldo
A
Janin
Anne
A
Levy
Bernard
B
Girot
Robert
R
Beuzard
Yves
Y
Leboeuf
Christophe
C
Henri
Annie
A
Germain
Stéphane
S
Dussaule
Jean-Claude
JC
Tharaux
Pierre-Louis
PL
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
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan