Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels
| Autor: | Satish Kumar, B. Jyothi Lakshmi, Komjeti Suman, Dhananjay Shukla, Rashna Bhandari, Somadri Ghosh, R. Manorama |
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| Rok vydání: | 2013 |
| Předmět: |
Blood Platelets
Male Bleeding Time Phytic Acid Immunology Biochemistry Mice chemistry.chemical_compound Polyphosphates Thromboembolism Animals Inositol Platelet Platelet activation Hemostatic function Blood Coagulation Mice Knockout Hemostasis Phosphotransferases (Phosphate Group Acceptor) Inositol Hexakisphosphate Kinase 1 Polyphosphate Thrombin Cell Biology Hematology Mice Inbred C57BL P-Selectin chemistry Pulmonary Embolism |
| Zdroj: | Blood. 122:1478-1486 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2013-01-481549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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