The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model.
Pulmonary arterial hypertension (PAH) is suspected to be a strong mortality determinant of hemolytic disorders. However, direct contribution of acute intravascular hemolysis to fatal PAH has not been investigated. The roles of nitric oxide (NO) insufficiency and platelet activation in hemolysis-associated fatal PAH have been suspected but not been experimentally studied. We recently generated a unique intravascular hemolysis mouse model in which the membrane toxin, intermedilysin (ILY), exclusively lyses the erythrocytes of transgenically expressing human CD59 mice (ThCD59(RBC)), thereby inducing ILY-dose-dependent massive hemolysis. Using this murine hemolysis model, we found that the acute increase in pulmonary arterial pressure leading to right ventricle failure caused sudden death. Reduced NO bioavailability and massive platelet activation/aggregation leading to the formation of massive thrombosis specifically in the pulmonary microvasculature played the critical roles in pathogenesis of acute hemolysis-associated fatal PAH. Therapeutic interventions enhancing NO bioactivity or inhibiting platelet activation prevented sudden death or prolonged survival time via the suppression of the acute increase in pulmonary arterial pressure and improvement of right ventricle function. These findings further highlight the importance of the inhibition of platelet activation and the enhancement of NO bioavailability for the treatment and prevention of hemolysis-associated (fatal) PAH.
Hu
Weiguo
W
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jin
Richard
R
Zhang
Jinyan
J
You
Tao
T
Peng
Zhihai
Z
Ge
Xiaowen
X
Bronson
Roderick T
RT
Halperin
Jose A
JA
Loscalzo
Joseph
J
Qin
Xuebin
X
D000818:Animals; D001430:Bacteriocins / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D018957:CD59 Antigens / Q000502:physiology; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006461:Hemolysis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000401:mortality* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000493:pharmacokinetics*; D015539:Platelet Activation; D010974:Platelet Aggregation; D011651:Pulmonary Artery / Q000503:physiopathology*; D015996:Survival Rate; D014018:Tissue Distribution
D001430:Bacteriocins; D018957:CD59 Antigens; D005343:Fibrinolytic Agents; C403910:intermedilysin protein, Streptococcus intermedius; D009569:Nitric Oxide