Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.

Legrand, Chantal; Morandi, Verônica; Mendelovitz, Simona; Shaked, Hadassa; Hartman, Jacob R.; Panet, Amos

doi:10.1161/01.atv.14.11.1784

Cited by 30 publications

(22 citation statements)

References 42 publications

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“…The interaction between TSP-1 and fibrinogen-occupied platelets was almost completely inhibited by heparin (Fig. 3a), which binds with high affinity to the N-terminal region of TSP-1 (34).…”

Section: Resultsmentioning

confidence: 97%

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

Narizhneva

Byers-Ward

Quinn

et al. 2004

Journal of Biological Chemistry

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A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an increased risk for development of premature, familial heart attacks. We now have identified both functional and structural differences between the Ser-700 and Asn-700 thrombospondin-1 variants. The Ser-700 variant increased the rate and extent of platelet aggregation and showed increased surface expression on platelets compared with the Asn-700 variant. These differences could be ascribed to an enhanced interaction of the Ser-700 variant with fibrinogen on the platelet surface and are consistent with a prothrombotic phenotype in Ser-700 individuals. The Ser-700 variant thrombospondin-1 was conformationally more labile than the Asn-700 variant as demonstrated by increased susceptibility to proteolytic digestion and enhanced susceptibility to unfolding by denaturants. These data suggest a potential molecular and cellular basis for a genetic risk factor associated with early onset myocardial infarction.

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Section: Resultsmentioning

confidence: 97%

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

Narizhneva

Byers-Ward

Quinn

et al. 2004

Journal of Biological Chemistry

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“…The participation of TSP in platelet aggregation has been demonstrated by a variety of studies reporting inhibition of platelet aggregation and secretion, by anti-TSP antibodies (18 -23) and synthetic or recombinant peptides of TSP (6,24). Leung (19) suggested that the interaction of TSP with Fg on the surface of activated platelets stabilizes the binding of Fg to its receptor, the activated integrin GPIIbIIIa (GPIIbIIIa*), with only Fg participating in direct cross-bridges.…”

Section: Thrombospondin-1 (Tsp)mentioning

confidence: 99%

A Model of Platelet Aggregation Involving Multiple Interactions of Thrombospondin-1, Fibrinogen, and GPIIbIIIa Receptor

Bonnefoy

Hantgan

Legrand

et al. 2001

Journal of Biological Chemistry

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Thrombospondin-1 (TSP) may, after secretion from platelet ␣ granules, participate in platelet aggregation, but its mode of action is poorly understood. We evaluated the capacity of TSP to form inter-platelet crossbridges through its interaction with fibrinogen (Fg), using either Fg-coated beads or Fg bound to the activated GPIIbIIIa integrin (GPIIbIIIa*) immobilized on beads or on activated fixed platelets (AFP), i.e. in a system free of platelet signaling and secretion mechanisms. Aggregation at physiological shear rates (100 -2000 s ؊1 ) was studied in a microcouette device and monitored by flow cytometry. Soluble TSP bound to and induced aggregation of Fg-coated beads dose-dependently, which could be blocked by the amino-terminal heparin-binding domain of TSP, TSP18. Soluble TSP did not bind to GPIIbIIIa*-coated beads or AFP, unless they were preincubated with Fg. The interaction of soluble TSP with Fg-GPIIbIIIa*-coated beads or Fg-AFP resulted in the formation of aggregates via Fg-TSP-Fg cross-bridges, as demonstrated in a system where direct cross-bridges mediated by GPIIbIIIa*-Fg on one particle and free GPIIbIIIa* on a second particle were blocked by the RGD mimetic Ro 44 -9883. Soluble TSP increased the efficiency of Fg-mediated aggregation of AFP by 30 -110% over all shear rates and GPIIbIIIa* occupancies evaluated. Surprisingly, TSP binding to Fg already bound to its GPIIbIIIa* receptor appears to block the ability of this occupied Fg to recognize another GPIIbIIIa* receptor, but this TSP can indeed cross-bridge to another Fg molecule on a second platelet. Finally, TSP-coated beads could directly coaggregate at shear rates from 100 to 2000 s ؊1 . Our studies provide a model for the contribution of secreted TSP in reinforcing inter-platelet interactions in flowing blood, through direct Fg-TSP-Fg and TSP-TSP cross-bridges.

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“…Earlier studies reported contradictory evidence regarding the role of TSP1 in platelet activation (135,280), and the first evaluation of platelet function in Thbs1 -/-mice reported normal hemostatic function as assessed by tail bleeding and thrombin activation of washed platelets (127). Therefore, TSP1 was concluded to not be required for normal platelet function.…”

Section: +mentioning

confidence: 99%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.

Cited by 30 publications

References 42 publications

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

A Model of Platelet Aggregation Involving Multiple Interactions of Thrombospondin-1, Fibrinogen, and GPIIbIIIa Receptor

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

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