Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: Implications for ischemic vascular diseases
Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: Implications for ischemic vascular diseases
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DOI：
10.1124/jpet.102.043729
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发表时间：
2003-04-01
影响因子：
3.5
通讯作者：
Levi, R
中科院分区：
文献类型：
--
作者：
Marcus, AJ;Broekman, MJ;Levi, R
血小板负责维持血管完整性。在血小板减少状态下，血管通透性和脆性增加，可能是由于缺乏这种血小板功能。对血管的化学或物理损伤会诱导血小板活化和血小板募集。这有利于止血（止血），但当动脉粥样硬化斑块溃烂或破裂时，它会成为血管闭塞（血栓形成）的激动剂。 20 世纪 80 年代后期的实验逐渐表明，即使在没有前列环素或一氧化氮的情况下，内皮细胞 CD39（一种外切 ADP 酶）也会降低血小板对大多数激动剂的反应性。如本文所讨论的，CD39快速并优先将从活化血小板释放的ATP和ADP代谢为AMP，从而显着减少甚至消除血小板聚集和募集。由于 ADP 是血小板募集和血栓形成的最终共同激动剂，这一发现凸显了 CD39 的重要性。人类 CD39 的重组可溶形式 solCD39 具有与该分子的全长形式相同的酶学和生物学特性，并强烈抑制由 ADP、胶原蛋白、花生四烯酸或 TRAP（凝血酶受体激动剂肽）诱导的人血小板聚集。在从豚鼠心脏分离的交感神经末梢中，神经元 ATP 增强去甲肾上腺素胞吐作用，solCD39 显着减弱去甲肾上腺素释放。这表明 NTPDase（核苷三磷酸二磷酸水解酶）可以通过减少 ATP 介导的去甲肾上腺素释放来发挥心脏保护作用，从而为心肌缺血及其后果提供一种新的治疗方法。在小鼠中风模型中，由于血小板过度募集，solCD39 减少了中风后遗症，并且没有增加脑出血。通过删除腺苷三磷酸双磷酸酶保守区 2 至 4 产生的 CD39 缺失小鼠与对照组相比，表现出缺血后灌注减少和脑梗塞体积增加。用 solCD39 对 CD39 缺失小鼠进行“重建”，逆转了这些变化。我们假设 solCD39 有潜力作为血栓素质的新型治疗剂。
Platelets are responsible for maintaining vascular integrity. In thrombocytopenic states, vascular permeability and fragility increase, presumably due to the absence of this platelet function. Chemical or physical injury to a blood vessel induces platelet activation and platelet recruitment. This is beneficial for the arrest of bleeding (hemostasis), but when an atherosclerotic plaque is ulcerated or fissured, it becomes an agonist for vascular occlusion ( thrombosis). Experiments in the late 1980s cumulatively indicated that endothelial cell CD39 - an ecto-ADPase - reduced platelet reactivity to most agonists, even in the absence of prostacyclin or nitric oxide. As discussed herein, CD39 rapidly and preferentially metabolizes ATP and ADP released from activated platelets to AMP, thereby drastically reducing or even abolishing platelet aggregation and recruitment. Since ADP is the final common agonist for platelet recruitment and thrombus formation, this finding highlights the significance of CD39. A recombinant, soluble form of human CD39, solCD39, has enzymatic and biological properties identical to the full-length form of the molecule and strongly inhibits human platelet aggregation induced by ADP, collagen, arachidonate, or TRAP ( thrombin receptor agonist peptide). In sympathetic nerve endings isolated from guinea pig hearts, where neuronal ATP enhances norepinephrine exocytosis, solCD39 markedly attenuated norepinephrine release. This suggests that NTPDase ( nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences. In a murine model of stroke, driven by excessive platelet recruitment, solCD39 reduced the sequelae of stroke, without an increase in intracerebral hemorrhage. CD39 null mice, generated by deletion of apyrase-conserved regions 2 to 4, exhibited a decrease in postischemic perfusion and an increase in cerebral infarct volume when compared with controls. "Reconstitution" of CD39 null mice with solCD39 reversed these changes. We hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic diatheses.