Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

Enjyoji, Keiichi; Sévigny, Jean; Lin, Yuan; Frenette, Paul S.; Christie, Patricia D.; Esch, Jan Schulte Am; Imai, Masato; Edelberg, Jay M.; Rayburn, Helen; Lech, Miroslaw; Beeler, David; Csizmadia, Eva; Wagner, Denisa D.; Robson, Simon C.; Rosenberg, Robert D.

doi:10.1038/12447

Cited by 523 publications

(562 citation statements)

References 44 publications

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“…Examples of cellular co-expression of NTPDases identified by immunocytochemistry include epithelial cells in a variety of tissues [40]. NTPDase1 is the most thoroughly investigated enzyme and considerable insight has been gained from the generation of knockout mice [41,42]. NTPDase1 is a lymphocyte activation marker and found to be expressed on natural killer cells, monocytes, dendritic cells, and subsets of activated T cells.…”

Section: General Properties and Functional Rolementioning

confidence: 99%

“…There are multiple examples showing that application of inhibitors such as the nucleotide analogue ARL 67156 potentiate nucleotide-mediated neurotransmission [170][171][172][173]. Deletion of NTPDase1 in mice revealed a key role of this enzyme in the prevention of thrombosis [41,42], in purine signaling in angiogenesis [174], vascular permeability [175,176], vascular relaxation [49], in the control of macrophage function [177], or also in promoting tumor growth [178]. Accordingly, transgenic mice expressing human NTPDase1 exhibited impaired platelet aggregation and were protected from thrombosis in a transplantation setting [179].…”

Section: Downstream Signaling Nucleotidesmentioning

confidence: 99%

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Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

890

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Section: General Properties and Functional Rolementioning

confidence: 99%

Section: Downstream Signaling Nucleotidesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

890

922

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“…6 CD39 is the dominant vascular endothelial and immune ectonucleotidase and hydrolyzes both ATP and ADP in the plasma to AMP, ultimately to adenosine via CD73. 6 Another NTPDase associated with the vasculature and expressed by HSC and portal fibroblasts is the cell-associated ecto-ATPase (CD39L1 or NTPDase2). 7 Extracellular nucleotides regulate inflammation and immunity via purinergic/ pyrimidinergic P2-receptors (P2X-R and -P2Y-R receptors).…”

Section: Introductionmentioning

confidence: 99%

Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-Null Mice

et al. 2008

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Background & Aims-Extracellular nucleotides are released from injured cells and bind to purinergic-type 2 receptors (P2-R) that modulate inflammatory responses. Ectonucleotidases, such as CD39/NTPDase1, hydrolyze extracellular nucleotides to integrate purinergic signaling responses. As the role of extracellular nucleotides and CD39 in mediating inflammation and fibrosis are poorly understood, we studied the impact of CD39 gene deletion in a model of pancreatic disease.

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“…We have previously shown that deletion of CD39 results in disordered purinergic signaling responses that compromise vascular thromboregulation, promote inflammatory responses, and impact hepatic metabolism [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia

Sun

Imai

Nowak-Machen

et al. 2011

Purinergic Signalling

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Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5′-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/−) and matched Cd39-null mice (−/−); (n=25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n=6) and Cd39-null mice (n=6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P 31 -NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/− and 84% of Cd39-null mice required euthanasia or died within 4 h postreperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI.

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Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

Cited by 523 publications

References 44 publications

Cellular function and molecular structure of ecto-nucleotidases

Cellular function and molecular structure of ecto-nucleotidases

Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-Null Mice

Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia

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