Role of CD39 (NTPDase-1) in Thromboregulation, Cerebroprotection, and Cardioprotection

Aaron J. Marcus; M. Johan Broekman; Joan H. F. Drosopoulos; Kim E. Olson; Naziba Islam; David J. Pinsky; Roberto Levi

doi:10.1055/s-2005-869528

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2005; 31(2): 234-246
DOI: 10.1055/s-2005-869528

Role of CD39 (NTPDase-1) in Thromboregulation, Cerebroprotection, and Cardioprotection

Aaron J. Marcus¹ ^, ² ^, ³ ^, ⁵ ^, ⁶ , M. Johan Broekman² ^, ⁶ , Joan H. F. Drosopoulos² ^, ⁶ , Kim E. Olson² ^, ⁶ , Naziba Islam² ^, ⁶ , David J. Pinsky⁷ , Roberto Levi⁴

¹Chief, Hematology/Oncology, Weill Medical College of Cornell University, New York, New York
²Department of Medicine, Weill Medical College of Cornell University, New York, New York
³Department of Pathology, Weill Medical College of Cornell University, New York, New York
⁴Department of Pharmacology, Weill Medical College of Cornell University, New York, New York
⁵Medical Service/Hematology-Oncology, VA New York Harbor Healthcare System, New York, New York
⁶Research Service-Hematology/Oncology, VA New York Harbor Healthcare System, New York, New York
⁷Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan

Abstract

ABSTRACT

Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to coronary, carotid, or peripheral arteries promotes excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently, inadequate therapeutic approaches to stroke and coronary artery disease (CAD) are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions among platelets and other blood cells. This led to concepts of transcellular metabolism and thromboregulation. Thrombosis has a proinflammatory component whereby biologically active substances are synthesized by different cell types that could not individually synthesize the metabolite(s). Endothelium controls platelet reactivity via at least three biochemical systems: autacoids leading to production of prostacyclin and nitric oxide (NO) and endothelial ecto-adenosine phosphatase (ADPase)/CD39/nucleoside triphosphate diphosphohydrolase (NTPDase-1). The autacoids are fluid phase reactants, not produced by tissues in the basal state, but are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, they exert fleeting actions in the immediate milieu and are rapidly inactivated. CD39 is an integral component of the endothelial cell (EC) surface and is substrate activated. It maintains vascular fluidity in the complete absence of prostacyclin and NO, indicating that the latter are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient and local action and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in animal models. It metabolically neutralizes a prothrombotic releasate via deletion of ADP-the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced adenosine triphosphate (ATP)- and ischemia-induced norepinephrine release in the heart. This action can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in cd39 null mice. Thus, CD39 represents the next generation of cardioprotective and cerebroprotective molecules. This article focuses on our interpretations of recent data and their implications for therapeutics.

KEYWORDS

Thrombosis - ecto-nucleotidase - stroke - coronary artery disease - platelet function inhibitors

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Aaron J MarcusM.D.

Chief, Hematology/Oncology, VA New York Harbor Healthcare System and Weill Medical College of Cornell University

423 East 23rd Street, New York, NY 10010

eMail: ajmarcus@med.cornell.edu