ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury
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Published:2022-04-05
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Rohlfing Anne-KatrinORCID, Kolb KyraORCID, Sigle Manuel, Ziegler Melanie, Bild Alexander, Münzer Patrick, Sudmann Jessica, Dicenta Valerie, Harm Tobias, Manke Mailin-ChristinORCID, Geue Sascha, Kremser MarcelORCID, Chatterjee MadhumitaORCID, Liang ChunguangORCID, von Eysmondt HendrikORCID, Dandekar ThomasORCID, Heinzmann David, Günter Manina, von Ungern-Sternberg Saskia, Büttcher Manuela, Castor Tatsiana, Mencl Stine, Langhauser Friederike, Sies KatharinaORCID, Ashour Diyaa, Beker Mustafa Caglar, Lämmerhofer MichaelORCID, Autenrieth Stella E., Schäffer Tilman E.ORCID, Laufer StefanORCID, Szklanna Paulina, Maguire Patricia, Heikenwalder MatthiasORCID, Müller Karin Anne Lydia, Hermann Dirk M., Kilic Ertugrul, Stumm RalfORCID, Ramos Gustavo, Kleinschnitz Christoph, Borst Oliver, Langer Harald F.ORCID, Rath Dominik, Gawaz MeinradORCID
Abstract
AbstractPlatelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.
Funder
Deutsche Forschungsgemeinschaft
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference60 articles.
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