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Thromb Haemost 2013; 109(06): 1108-1119
DOI: 10.1160/TH12-10-0751
Platelets and Blood Cells
Schattauer GmbH

Autocrine amplification of integrin αIIbβ3 activation and platelet adhesive responses by deoxyribose-1-phosphate

Dina S. Vara
1   Department of Pharmacy and Pharmacology, University of Bath, Bath, UK
,
Michelangelo Campanella
2   Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, London, UK
3   Consortium for Mitochondrial Research (CfMR), University College London, London, UK
,
Ilaria Canobbio
4   Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
,
Warwick B. Dunn
5   Institute of Human Development, The University of Manchester, Manchester, UK
6   Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, Manchester, UK
,
Giuseppe Pizzorno
7   Department of Drug Discovery, Nevada Cancer Institute, Las Vegas, Nevada, USA
,
Michio Hirano
8   Department of Neurology, Columbia University Medical Center, New York, New York, USA
,
Giordano Pula
1   Department of Pharmacy and Pharmacology, University of Bath, Bath, UK
› Author Affiliations Financial support: The work with transgenic animals was sponsored by the Royal Society (RG090131), whereas the studies on human platelets were supported by the BBSRC (BB/J002690/1).
Further Information

Publication History

Received: 17 October 2012

Accepted after major revision: 13 February 2013

Publication Date:
22 November 2017 (online)

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Summary

Using direct injection mass spectrometry (DIMS) we discovered that deoxyribose-1-phosphate (dRP) is released by platelets upon activation. Interestingly, the addition of exogenous dRP to human platelets significantly increased platelet aggregation and integrin αIIbβ3 activation in response to thrombin. In parallel, genetically modified platelets with double genetic deletion of thymidine phosphorylase and uridine phosphorylase were characterised by reduced release of dRP, impaired aggregation and decreased integrin αIIbβ3 activation in response to thrombin. In vitro platelet adhesion onto fibrinogen and collagen under physiological flow conditions was potentiated by treatment of human platelets with exogenous dRP and impaired in transgenic platelets with reduced dRP release. Human and mouse platelets responded to dRP treatment with a sizeable increase in reactive oxygen species (ROS) generation and the pre-treament with the antioxidant apocynin abolished the effect of dRP on aggregation and integrin activation. Experiments directly assessing the activation of the small G protein Rap1b and protein kinase C suggested that dRP increases the basal levels of activity of these two pivotal platelet-activating pathways in a redox-dependent manner. Taken together, we present evidence that dRP is a novel autocrine amplifier of platelet activity, which acts on platelet redox levels and modulates integrin αIIbβ3.

Keywords

Platelets - reactive oxygen species - deoxyribose-1-phosphate - integrin - redox signalling

 

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