Qin Xuebin, Hu Weiguo, Song Wenping, Blair Price, Wu Gongxiong, Hu Xuemei, Song Yanli, Bauer Selena, Feelisch Martin, Leopold Jane A, Loscalzo Joseph, Halperin Jose A
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Am J Hematol. 2009 Apr;84(4):221-7. doi: 10.1002/ajh.21363.
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.
CD59是补体膜攻击复合物（MAC）的一种膜蛋白抑制剂。据报道，mCd59基因敲除小鼠表现出溶血性贫血和血小板活化。这种表型与人类称为阵发性夜间血红蛋白尿（PNH）的溶血性贫血相似，在PNH中血小板活化和血栓形成起着关键的致病作用。长期以来一直怀疑但未正式证实补体和一氧化氮（NO）都与PNH血栓形成有关。利用在补体充足（C3(+/+)）和缺乏（C3(-/-)）背景下的mCd59a和mCd59b双基因敲除小鼠（mCd59ab(-/-)小鼠），我们证明mCd59ab(-/-)血小板对补体介导的活化敏感，并为mCd59ab(-/-)小鼠体内可能的血小板活化提供了证据。使用L-NAME（一种NO合酶抑制剂）与NOC-18或SNAP（NO供体）的组合，我们进一步证明NO调节补体介导的血小板活化。这些结果表明，PNH患者的血栓形成倾向可能是由于补体介导的血小板活化增加和溶血导致的NO生物利用度降低共同作用的结果。
