Balancing role of nitric oxide in complement-mediated activation of platelets from mCd59a and mCd59b double-knockout mice.
CD59 is a membrane protein inhibitor of the membrane attack complex (MAC) of complement. mCd59 knockout mice reportedly exhibit hemolytic anemia and platelet activation. This phenotype is comparable to the human hemolytic anemia known as paroxysmal nocturnal hemoglobinuria (PNH), in which platelet activation and thrombosis play a critical pathogenic role. It has long been suspected but not formally demonstrated that both complement and nitric oxide (NO) contribute to PNH thrombosis. Using mCd59a and mCd59b double knockout mice (mCd59ab(-/-) mice) in complement sufficient (C3(+/+)) and deficient (C3(-/-)) backgrounds, we document that mCd59ab(-/-) platelets are sensitive to complement-mediated activation and provide evidence for possible in vivo platelet activation in mCd59ab(-/-) mice. Using a combination of L-NAME (a NO-synthase inhibitor) and NOC-18 or SNAP (NO-donors), we further demonstrate that NO regulates complement-mediated activation of platelets. These results indicate that the thrombotic diathesis of PNH patients could be due to a combination of increased complement-mediated platelet activation and reduced NO-bioavailability as a consequence of hemolysis.
Qin
Xuebin
X
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. xuebin_qin@hms.harvard.edu
Hu
Weiguo
W
Song
Wenping
W
Blair
Price
P
Wu
Gongxiong
G
Hu
Xuemei
X
Song
Yanli
Y
Bauer
Selena
S
Feelisch
Martin
M
Leopold
Jane A
JA
Loscalzo
Joseph
J
Halperin
Jose A
JA
D000818:Animals; D001792:Blood Platelets / Q000276:immunology*; D018957:CD59 Antigens / Q000235:genetics / Q000502:physiology*; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000276:immunology; D004195:Disease Models, Animal; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000150:complications* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009603:Nitroso Compounds / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D019851:Thrombophilia / Q000209:etiology* / Q000276:immunology
D018957:CD59 Antigens; C539311:CD59a protein, mouse; C539312:CD59b protein, mouse; D003176:Complement C3; D015938:Complement Membrane Attack Complex; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester