Abstract
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.
Footnotes
-
This study was supported by National Institutes of Health Grants HL47073, HL46403, and NS41462 (to A.J.M., M.J.B., J.H.F.D., and N.I.), NS41460, HL59488, and HL69448 (to D.J.P.), and HL34215 and HL46403 (to C.S. and R.L.), and by Merit Review grants from the Department of Veterans Affairs (to A.J.M., M.J.B., J.H.F.D., N.I.).
-
DOI: 10.1124/jpet.102.043729
- Abbreviations:
- vWF
- von Willebrand Factor
- TXA2
- thromboxane A2
- PGI2
- prostaglandin I2
- HUVEC
- human umbilical vein endothelial cells
- ACR
- apyrase-conserved regions
- TRAP
- thrombin receptor agonist peptide
- PRP
- platelet-rich plasma
- NE
- norepinephrine
- PPADS
- pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid
- ARL-67156
- 6-N,N-diethyl-β-γ-dibromomethylene-d-adenosine-5′-triphosphate
- CD39
- cluster of differentiation number 39
- DEPC
- diethyl pyrocarbonate
- MRS-2179
- 2′-deoxy-N6-methyladenosine-3′,5′-diphosphate
- NTPDase
- nucleoside triphosphate diphosphohydrolase
- Received August 27, 2002.
- Accepted November 15, 2002.
- U.S. Government
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|