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

Dina S. Vara; Michelangelo Campanella; Ilaria Canobbio; Warwick B. Dunn; Giuseppe Pizzorno; Michio Hirano; Giordano Pula

doi:10.1160/TH12-10-0751

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Department of Pharmacy and Pharmacology, University of Bath, Bath, UK

,

Michelangelo Campanella

²Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, London, UK

³Consortium for Mitochondrial Research (CfMR), University College London, London, UK

,

Ilaria Canobbio

⁴Department of Biology and Biotechnology, University of Pavia, Pavia, Italy

,

Warwick B. Dunn

⁵Institute of Human Development, The University of Manchester, Manchester, UK

⁶Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, Manchester, UK

,

Giuseppe Pizzorno

⁷Department of Drug Discovery, Nevada Cancer Institute, Las Vegas, Nevada, USA

,

Michio Hirano

⁸Department of Neurology, Columbia University Medical Center, New York, New York, USA

,

Giordano Pula

¹Department of Pharmacy and Pharmacology, University of Bath, Bath, UK

› Institutsangaben

Abstract

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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Referenzen

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