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Ghosh, S. and Shukla, D. and Suman, K. and Lakshmi, B.J. and Manorama, R. and Kumar, S. and Bhandari, Rashna (2013) Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels. Blood, 122 (8). pp. 1478-1486. ISSN 0006-4971

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Abstract

Polyphosphate (polyP), a polymer of orthophosphate moieties released from the dense granules of activated platelets, is a procoagulant agent. Inositol pyrophosphates, another group of phosphate-rich molecules, consist of mono- and diphosphates substituted on an inositol ring. Diphosphoinositol pentakisphosphate (IP7), the most abundant inositol pyrophosphate, is synthesized on phosphorylation of inositol hexakisphosphate (IP6) by IP6 kinases, of which there are 3 mammalian isoforms (IP6K1/2/3) and a single yeast isoform. Yeast lacking IP6 kinase are devoid of polyP, suggesting a role for IP6 kinase in maintaining polyP levels. We theorized that the molecular link between IP6 kinase and polyP is conserved in mammals and investigated whether polyP-dependent platelet function is altered in IP6K1 knockout (Ip6k1(-/-)) mice. We observe a significant reduction in platelet polyP levels in Ip6k1(-/-) mice, along with slower platelet aggregation and lengthened plasma clotting time. Incorporation of polyP into fibrin clots was reduced in Ip6k1(-/-) mice, thereby altering clot ultrastructure, which was rescued on the addition of exogenous polyP. In vivo assays revealed longer tail bleeding time and resistance to thromboembolism in Ip6k1(-/-) mice. Taken together, our data suggest a novel role for IP6K1 in regulation of mammalian hemostasis via its control of platelet polyP levels.

Item Type: Article
Additional Information: [Open Access from Publisher]
Depositing User: Dr P Divakar
Date Deposited: 15 Sep 2015 10:12
Last Modified: 21 Sep 2015 05:59
URI: http://cdfd.sciencecentral.in/id/eprint/524

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