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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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Loss of ATPDase activity during reperfusion injury in vivo. Upper panels show the extent of enzyme histochemical activity (cerium chloride  method) within representative glomeruli of rat kidneys which were (a) freshly harvested, or (b) subjected to 1 h of ischemia and a further hour of reperfusion. Compared to the moderate to dense enzyme expression by rat vascular EC in control glomeruli (a), reperfusion injury and associated oxidative  stress reduced ATPDase activity to negligible levels (b); arrows indicate neutrophils within capillary loops of kidney subjected to reperfusion injury.  Lower panels are corresponding Hematoxylin- and Eosin-stained sections, showing (c) good preservation of glomerular structure and absence of leukocytes, and (d) association of reperfusion injury with focal platelet microthrombi which fill some capillary loops and the presence of neutrophils (arrows). All  panels ×200.
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Figure 8: Loss of ATPDase activity during reperfusion injury in vivo. Upper panels show the extent of enzyme histochemical activity (cerium chloride method) within representative glomeruli of rat kidneys which were (a) freshly harvested, or (b) subjected to 1 h of ischemia and a further hour of reperfusion. Compared to the moderate to dense enzyme expression by rat vascular EC in control glomeruli (a), reperfusion injury and associated oxidative stress reduced ATPDase activity to negligible levels (b); arrows indicate neutrophils within capillary loops of kidney subjected to reperfusion injury. Lower panels are corresponding Hematoxylin- and Eosin-stained sections, showing (c) good preservation of glomerular structure and absence of leukocytes, and (d) association of reperfusion injury with focal platelet microthrombi which fill some capillary loops and the presence of neutrophils (arrows). All panels ×200.

Mentions: Using a cerium-based histochemical method, strongly positive staining for the ADP hydrolysis reaction product specifically generated by ATPDase activity, was observed in association with the vasculature of glomeruli from normal rat kidneys. After 1 h of ischemia and 1 h of subsequent reperfusion, a marked reduction in staining was noted (Fig. 8, a and b). In parallel, corresponding light microscopy showed that control glomeruli lacked neutrophils, whereas a considerable number of neutrophils associated with platelet deposits were noted after the episode of ischemia-reperfusion (Fig. 8, c and d).


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)

Loss of ATPDase activity during reperfusion injury in vivo. Upper panels show the extent of enzyme histochemical activity (cerium chloride  method) within representative glomeruli of rat kidneys which were (a) freshly harvested, or (b) subjected to 1 h of ischemia and a further hour of reperfusion. Compared to the moderate to dense enzyme expression by rat vascular EC in control glomeruli (a), reperfusion injury and associated oxidative  stress reduced ATPDase activity to negligible levels (b); arrows indicate neutrophils within capillary loops of kidney subjected to reperfusion injury.  Lower panels are corresponding Hematoxylin- and Eosin-stained sections, showing (c) good preservation of glomerular structure and absence of leukocytes, and (d) association of reperfusion injury with focal platelet microthrombi which fill some capillary loops and the presence of neutrophils (arrows). All  panels ×200.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 8: Loss of ATPDase activity during reperfusion injury in vivo. Upper panels show the extent of enzyme histochemical activity (cerium chloride method) within representative glomeruli of rat kidneys which were (a) freshly harvested, or (b) subjected to 1 h of ischemia and a further hour of reperfusion. Compared to the moderate to dense enzyme expression by rat vascular EC in control glomeruli (a), reperfusion injury and associated oxidative stress reduced ATPDase activity to negligible levels (b); arrows indicate neutrophils within capillary loops of kidney subjected to reperfusion injury. Lower panels are corresponding Hematoxylin- and Eosin-stained sections, showing (c) good preservation of glomerular structure and absence of leukocytes, and (d) association of reperfusion injury with focal platelet microthrombi which fill some capillary loops and the presence of neutrophils (arrows). All panels ×200.
Mentions: Using a cerium-based histochemical method, strongly positive staining for the ADP hydrolysis reaction product specifically generated by ATPDase activity, was observed in association with the vasculature of glomeruli from normal rat kidneys. After 1 h of ischemia and 1 h of subsequent reperfusion, a marked reduction in staining was noted (Fig. 8, a and b). In parallel, corresponding light microscopy showed that control glomeruli lacked neutrophils, whereas a considerable number of neutrophils associated with platelet deposits were noted after the episode of ischemia-reperfusion (Fig. 8, c and d).

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