Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate
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Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate. / Mailer, Reiner K; Allende, Mikel; Heestermans, Marco; Schweizer, Michaela; Deppermann, Carsten; Frye, Maike; Pula, Giordano; Odeberg, Jacob; Gelderblom, Mathias; Rose-John, Stefan; Sickmann, Albert; Blankenberg, Stefan; Huber, Tobias B; Kubisch, Christian; Maas, Coen; Gambaryan, Stepan; Firsov, Dmitri; Stavrou, Evi X; Butler, Lynn M; Renné, Thomas.
in: BLOOD, Jahrgang 137, Nr. 10, 11.03.2021, S. 1392-1405.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate
AU - Mailer, Reiner K
AU - Allende, Mikel
AU - Heestermans, Marco
AU - Schweizer, Michaela
AU - Deppermann, Carsten
AU - Frye, Maike
AU - Pula, Giordano
AU - Odeberg, Jacob
AU - Gelderblom, Mathias
AU - Rose-John, Stefan
AU - Sickmann, Albert
AU - Blankenberg, Stefan
AU - Huber, Tobias B
AU - Kubisch, Christian
AU - Maas, Coen
AU - Gambaryan, Stepan
AU - Firsov, Dmitri
AU - Stavrou, Evi X
AU - Butler, Lynn M
AU - Renné, Thomas
PY - 2021/3/11
Y1 - 2021/3/11
N2 - Polyphosphate is a procoagulant inorganic polymer of linear-linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation; however, the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. In this study, xenotropic and polytropic retrovirus receptor 1 (XPR1) regulated polyphosphate in platelets and was implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. XPR1 messenger RNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation, and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism and reveal a fundamental role for phosphate homeostasis in thrombosis.
AB - Polyphosphate is a procoagulant inorganic polymer of linear-linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation; however, the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. In this study, xenotropic and polytropic retrovirus receptor 1 (XPR1) regulated polyphosphate in platelets and was implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. XPR1 messenger RNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation, and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism and reveal a fundamental role for phosphate homeostasis in thrombosis.
U2 - 10.1182/blood.2019004617
DO - 10.1182/blood.2019004617
M3 - SCORING: Journal article
C2 - 32932519
VL - 137
SP - 1392
EP - 1405
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 10
ER -