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Loss of ATP diphosphohydrolase activity with endothelial cell activation.

Robson SC, Kaczmarek E, Siegel JB, Candinas D, Koziak K, Millan M, Hancock WW, Bach FH - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Sandoz Center for Immunobiology, Boston, Massachusetts, USA.

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.

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Effect of pEC on platelet aggregation induced by ADP and  ADP-β-S (an ADP analog resistant to ATPDase activity). Platelets underwent comparable aggregation responses after stimulation with 1 μM ADP  and 5 μM ADP-β-S. Addition of pEC abrogated platelet responses to  ADP alone, but had minimal effects on ADP-β-S stimulated platelet aggregation. These data indicate a functional ATPDase associated with EC  is responsible, at least in part, for the inhibitory effects on platelet aggregation in vitro.
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Figure 1: Effect of pEC on platelet aggregation induced by ADP and ADP-β-S (an ADP analog resistant to ATPDase activity). Platelets underwent comparable aggregation responses after stimulation with 1 μM ADP and 5 μM ADP-β-S. Addition of pEC abrogated platelet responses to ADP alone, but had minimal effects on ADP-β-S stimulated platelet aggregation. These data indicate a functional ATPDase associated with EC is responsible, at least in part, for the inhibitory effects on platelet aggregation in vitro.

Mentions: Because of the importance of ADP as an agonist that amplifies and propagates platelet activation induced by itself or other agents (37), experiments were carried out to determine whether the inhibitory capacity of the xeno- and allogeneic aortic EC was dependent upon cellular ATPDase activity. To this end, ADP-β-S, a structural analog of ADP (38) that can activate platelet receptors but is not hydrolyzed by the ATPDase, was used to induce aggregation of platelets, both alone and in combination with pEC or hEC. The profound inhibitory effect of these EC on platelet aggregation was noted when ADP was used as the platelet agonist. However, this pattern of inhibition of platelet aggregation by EC was not observed when ADP-β-S was used as the agonist (Fig. 1). These data suggest that hydrolysis of ADP by ATPDase was responsible, at least in part, for the inhibitory potential of the EC.


Loss of ATP diphosphohydrolase activity with endothelial cell activation.

Robson SC, Kaczmarek E, Siegel JB, Candinas D, Koziak K, Millan M, Hancock WW, Bach FH - J. Exp. Med. (1997)

Effect of pEC on platelet aggregation induced by ADP and  ADP-β-S (an ADP analog resistant to ATPDase activity). Platelets underwent comparable aggregation responses after stimulation with 1 μM ADP  and 5 μM ADP-β-S. Addition of pEC abrogated platelet responses to  ADP alone, but had minimal effects on ADP-β-S stimulated platelet aggregation. These data indicate a functional ATPDase associated with EC  is responsible, at least in part, for the inhibitory effects on platelet aggregation in vitro.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196106&req=5

Figure 1: Effect of pEC on platelet aggregation induced by ADP and ADP-β-S (an ADP analog resistant to ATPDase activity). Platelets underwent comparable aggregation responses after stimulation with 1 μM ADP and 5 μM ADP-β-S. Addition of pEC abrogated platelet responses to ADP alone, but had minimal effects on ADP-β-S stimulated platelet aggregation. These data indicate a functional ATPDase associated with EC is responsible, at least in part, for the inhibitory effects on platelet aggregation in vitro.
Mentions: Because of the importance of ADP as an agonist that amplifies and propagates platelet activation induced by itself or other agents (37), experiments were carried out to determine whether the inhibitory capacity of the xeno- and allogeneic aortic EC was dependent upon cellular ATPDase activity. To this end, ADP-β-S, a structural analog of ADP (38) that can activate platelet receptors but is not hydrolyzed by the ATPDase, was used to induce aggregation of platelets, both alone and in combination with pEC or hEC. The profound inhibitory effect of these EC on platelet aggregation was noted when ADP was used as the platelet agonist. However, this pattern of inhibition of platelet aggregation by EC was not observed when ADP-β-S was used as the agonist (Fig. 1). These data suggest that hydrolysis of ADP by ATPDase was responsible, at least in part, for the inhibitory potential of the EC.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Sandoz Center for Immunobiology, Boston, Massachusetts, USA.

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.

Show MeSH
Related in: MedlinePlus