Inhibition of platelet function by recombinant soluble ecto-ADPase/CD39.

Gayle, rd R B; Maliszewski, Charles R.; Gimpel, Steven D.; Schoenborn, Michael A.; Caspary, R. Guy; Richards, Cynthia A.; Brasel, Kenneth; Price, Virginia L.; Drosopoulos, Joan H.F.; Islam, Naziba; Alyonycheva, T. N.; Broekman, M. Johan; Marcus, Aaron J.

doi:10.1172/jci1753

Cited by 176 publications

(161 citation statements)

References 36 publications

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“…Remarkably, these effects were not observed in mice treated with clopidogrel, showing that antagonising ADP receptor P2Y 12 is not sufficient to recapitulate the benefits of targeted CD39 in this model (Fig. 2c, d).…”

Section: Resultsmentioning

confidence: 92%

“…In the kidney, adenosine controls renin release, renal vascular tone and the rate of glomerular filtration. Recombinant soluble CD39 (solCD39) produced by deletion of the two transmembrane domains that anchor CD39 to the cell surface, inhibits platelet reactivity and recruitment, and provides protection in a murine model of stroke [8,11,12]. However, solCD39 promotes systemic bleeding in a concentration-dependent manner and therefore targeting CD39 to the site of endothelial activation will be a valid therapeutic option for IRI.…”

Section: Introductionmentioning

confidence: 99%

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Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury

Sashindranath

Dwyer

Dezfouli

et al. 2017

Purinergic Signalling

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Kidney ischemia-reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress. We designed a P-selectin targeted CD39 molecule (rsol.CD39-PSGL-1) consisting of recombinant soluble CD39 that incorporates 20 residues of PSGL-1 that bind P-selectin. We hypothesised that rsol.CD39-PSGL-1 would maintain endothelial integrity by focusing the ectonucleotidase platelet-inhibitory activity and reducing leukocyte adhesion at the injury site. The rsol.CD39-PSGL-1 displayed ADPase activity and inhibited platelet aggregation ex vivo, as well as bound with high specificity to soluble Pselectin and platelet surface P-selectin. Importantly, mice injected with rsol.CD39-PSGL-1 and subjected to renal IRI showed significantly less kidney damage both biochemically and histologically, compared to those injected with solCD39. Furthermore, the equivalent dose of rsol.CD39-PSGL-1 had no effect on tail template bleeding times. Hence, targeting recombinant CD39 to the injured vessel wall via PSGL-1 binding resulted in substantial preservation of renal function and morphology after IRI without toxicity. These studies indicate potential translational importance to clinical transplantation and nephrology.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury

Sashindranath

Dwyer

Dezfouli

et al. 2017

Purinergic Signalling

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“…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].…”

Section: Role Of Ntpdase1 In Thromboregulationmentioning

confidence: 99%

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

et al. 2007

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Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.

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“…As such, they have been shown or hypothesized to modulate many of the signaling and biosynthetic processes in which extracytoplasmic nucleotides play a role, including vascular homeostasis, cell size maintenance, neuronal signaling, immune function, and protein and lipid modification (3)(4)(5)(6)(7)(8). Consistent with the variety of tasks they perform on and in the cell, different family members exhibit different localizations and specificities: some reside on the plasma membrane and others in the Golgi, lysosomes, or endoplasmic reticulum, while each has a characteristic hierarchy of preferences for di-vs trinucleotides as well as for different bases (1,9-11).…”

Section: Introductionmentioning

confidence: 99%

Bilayer Mechanical Properties Regulate the Transmembrane Helix Mobility and Enzymatic State of CD39

Grinthal

Guidotti

2006

Biochemistry

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CD39 can exist in at least two distinct functional states depending on the presence and intact membrane integration of its two transmembrane helices. In native membranes, the transmembrane helices undergo dynamic rotational motions that are required for enzymatic activity and are regulated by substrate binding. In the present study we show that bilayer mechanical properties regulate conversion between the two enzymatic functional states by modulating transmembrane helix dynamics. Alteration of membrane properties by insertion of cone shaped or inverse cone shaped amphiphiles or by cholesterol removal switches CD39 to the same enzymatic state as does removing or solubilizing the transmembrane domains. The same membrane alterations increase the propensity of both transmembrane helices to rotate within the packed structure, resulting in a structure with greater mobility but not an altered primary conformation. Membrane alteration also abolishes the ability of substrate to stabilize the helices in their primary conformation, indicating a loss of coupling between substrate binding and transmembrane helix dynamics. Removal of either transmembrane helix mimics the effect of membrane alteration on the mobility and substrate sensitivity of the remaining helix, suggesting that the ends of the extracellular domain have intrinsic flexibility. We suggest that a mechanical bilayer property, potentially elasticity, regulates CD39 by altering the balance between stability and flexibility of its transmembrane helices and, in turn, of its active site. KeywordsCD39; NTPDase; transmembrane helices; bilayer; mechanical Of the various enzymes that process nucleotides at the cell surface and in the lumen of intracellular organelles, the ectonucleoside triphosphate diphosphohydrolases (eNTPDases) have emerged as the major family responsible and specific for breaking the terminal phosphoanhydride bonds of tri-and dinucleotides (1,2). As such, they have been shown or hypothesized to modulate many of the signaling and biosynthetic processes in which extracytoplasmic nucleotides play a role, including vascular homeostasis, cell size maintenance, neuronal signaling, immune function, and protein and lipid modification (3)(4)(5)(6)(7)(8). Consistent with the variety of tasks they perform on and in the cell, different family members exhibit different localizations and specificities: some reside on the plasma membrane and others in the Golgi, lysosomes, or endoplasmic reticulum, while each has a characteristic hierarchy of preferences for di-vs trinucleotides as well as for different bases (1,9-11). The defining structural feature shared by all family members is a set of five short sequences called apyrase conserved regions (ACRs) (12,13), two of which are thought to constitute phosphate binding loops based on homology to the nucleotide binding domain of the actin/hsp70/ † This work was supported by Grant HL08893 from the National Institutes of Health.*To whom correspondence should be addressed at 7 Divinity Ave., Cambridge, MA 02138. P...

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Inhibition of platelet function by recombinant soluble ecto-ADPase/CD39.

Cited by 176 publications

References 36 publications

Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury

Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury

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

Bilayer Mechanical Properties Regulate the Transmembrane Helix Mobility and Enzymatic State of CD39

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