Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation
Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation
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DOI：
10.1172/jci200419560
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发表时间：
2004-05-01
影响因子：
15.9
通讯作者：
d'Apice, AJF
中科院分区：
文献类型：
--
作者：
Dwyer, KM;Robson, SC;d'Apice, AJF
细胞外核苷酸在血栓形成和炎症中发挥重要作用，引发一系列效应，例如血小板活化和募集、内皮细胞活化和血管收缩。 CD39 是主要的血管核苷三磷酸二磷酸水解酶 (NTPDase)，可将 ATP 和 ADP 转化为 AMP，AMP 进一步降解为抗血栓和抗炎介质腺苷。 CD39 的缺失使小鼠对血管损伤极其敏感，并且 CD39 缺失的心脏异种移植物的存活率降低。相反，通过体细胞基因转移或施用可溶性 NTPDase 上调 CD39 在移植和炎症模型中具有重大益处。在这项研究中，我们研究了人类 CD39 (hCD39) 转基因表达在小鼠中的后果。重要的是，这些小鼠在正常情况下没有表现出明显的自发出血倾向。然而，hCD39 转基因小鼠确实表现出血小板聚集受损、出血时间延长以及对全身血栓栓塞的抵抗力。 bCD39 转基因供体心脏在血管排斥的小鼠心脏移植模型中基本上免受血栓形成，并且存活时间更长。 bCD39转基因小鼠的这些血栓调节表现表明，在临床血管疾病和控制危及灵长类猪异种移植物存活的严重血栓事件方面具有重要的治疗潜力。
Extracellular nucleotides play an important role in thrombosis and inflammation, triggering a range of effects such as platelet activation and recruitment, endothelial cell activation, and vasoconstriction. CD39, the major vascular nucleoside triphosphate diphosphohydrolase (NTPDase), converts ATP and ADP to AMP, which is further degraded to the antithrombotic and anti-inflammatory mediator adenosine. Deletion of CD39 renders mice exquisitely sensitive to vascular injury, and CD39-null cardiac xenografts show reduced survival. Conversely, upregulation of CD39 by somatic gene transfer or administration of soluble NTPDases has major benefits in models of transplantation and inflammation. In this study we examined the consequences of transgenic expression of human CD39 (hCD39) in mice. Importantly, these mice displayed no overt spontaneous bleeding tendency under normal circumstances. The hCD39 transgenic mice did, however, exhibit impaired platelet aggregation, prolonged bleeding times, and resistance to systemic thromboembolism. Donor hearts transgenic for bCD39 were substantially protected from thrombosis and survived longer in a mouse cardiac transplant model of vascular rejection. These thromboregulatory manifestations in bCD39 transgenic mice suggest important therapeutic potential in clinical vascular disease and in the control of serious thrombotic events that compromise the survival of porcine xenografts in primates.