Loss of ATP Diphosphohydrolase Activity with Endothelial Cell Activation

Abstract

Quiescent endothelial cells (EC) regulate blood flow and prevent intravascular thrombosis. This latter effect is mediated in a number of ways, including expression by EC of thrombomodulin and heparan sulfate, both of which are lost from the EC surface as part of the activation response to proinflammatory cytokines. Loss of these anticoagulant molecules potentiates the procoagulant properties of the injured vasculature. An additional thromboregulatory factor, ATP diphosphohydrolase (ATPDase; designated as EC 3.6.1.5) is also expressed by quiescent EC, and has the capacity to degrade the extracellular inflammatory mediators ATP and ADP to AMP, thereby inhibiting platelet activation and modulating vascular thrombosis. We describe here that the antithrombotic effects of the ATPDase, like heparan sulfate and thrombomodulin, are lost after EC activation, both in vitro and in vivo. Because platelet activation and aggregation are important components of the hemostatic changes that accompany inflammatory diseases, we suggest that the loss of vascular ATPDase may be crucial for the progression of vascular injury.

Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice

“…Such circumstances are frequently encountered in small arteries where platelet interactions with the vessel wall are dependent mainly on collagen and the von Willebrand factor (38) during such clinical interventions as angioplasty, where deep injury of the vessel wall often results in vascular reocclusion (39). In addition, platelet interactions with the vessel wall are mostly dependent on extracellular nucleotides and are regulated by the presence of ectonucleotidases, among which, CD39, the ATP diphosphohydrolase, has proved to be of major importance (40,41). Moreover, besides fibrin deposition in multiple organs because of deficiency in vascular protective effects, CD39 knock-out mice display an unexpected prolongation of the bleeding time because of selective desensitization of the P2Y 1 receptor (41).…”

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

“…The dual nature of ectoenzymes also needs to be rigorously tested, because some of their functions seem to perform independently of their enzymatic activity [106,110]. It is feasible that the large extracellular domains of ectoenzymes and their association with other membrane proteins or components can mediate responses without involvement of their catalytic activity [110].…”

“…Furthermore, the failure to develop specific inhibitors remains a major impediment to ongoing new discoveries on NTPDase activity [106]. Recently, it was demonstrated that P2 receptor antagonists inhibited human and plasma membrane bound NTPDases.…”

“…Studies have shown that CD39 inhibits platelet aggregation via three mechanisms: 1) by hydrolysis of ATP and/or ADP; 2) by participation in the enzymatic chain with 5'-nucleotidase to promote the formation of the anti-aggregatory metabolite adenosine [106] and 3) by blocking the binding of fibrinogen or the von Willebrand factor to platelets by inhibiting the activation of platelet glycoprotein (GP) IIB/IIIA adhesion receptors [80]. The first mechanism represents the blockade of platelet responsiveness to the prothrombotic agonist ADP, demonstrating the possibility of using CD39 as a potential antithrombotic agent [51,80,83,106].…”

“…The first mechanism represents the blockade of platelet responsiveness to the prothrombotic agonist ADP, demonstrating the possibility of using CD39 as a potential antithrombotic agent [51,80,83,106].…”