期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 1, 期 12, 页码 2497-2509出版社
BLACKWELL PUBL LTD
DOI: 10.1111/j.1538-7836.2003.00479.x
关键词
coronary artery disease; ecto-nucleotidase; stroke; thrombosis
资金
- NHLBI NIH HHS [HL 46403, HL69448, HL59488, HL34215, HL 47073] Funding Source: Medline
- NINDS NIH HHS [NS 41462] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R37HL047073, P01HL046403, R01HL069448, R01HL034215, R01HL047073, R01HL059488] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS041462] Funding Source: NIH RePORTER
Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to the coronary, carotid or peripheral arteries is followed by excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently inadequate therapeutic approaches to stroke and coronary artery disease are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions between platelets and other blood cells, leading to concepts of transcellular metabolism and thromboregulation. Thrombosis has a pro-inflammatory component whereby biologically active substances are synthesized by interactions between different cell types that could not individually synthesize the product(s). Endothelial cells control platelet reactivity via three biochemical systems-autacoids leading to production of prostacyclin and nitric oxide, and endothelial ecto-ADPase/CD39/NTPDase-1. The autacoids are fluid-phase reactants, not produced by tissues in the basal state. They are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, autacoids exert fleeting actions in the immediate milieu, and are rapidly inactivated. CD39 is an integral component of the endothelial cell surface and is substrate-activated. It maintains vascular fluidity in the complete absence of prostacyclin and nitric oxide, indicating that they are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient, local and fleeting action, and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in three different animal models. It metabolically neutralizes a prothrombotic platelet releasate via deletion of ADP-the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced ATP- and ischemia-induced norepinephrine release in the heart. This reduction can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in CD39 null mice. CD39 represents the next generation of cardioprotective and cerebroprotective molecules.
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