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Platelet ACKR3/CXCR7 favors antiplatelet lipids over an atherothrombotic lipidome and regulates thromboinflammation.
Cebo, Malgorzata; Dittrich, Kristina; Fu, Xiaoqing; Manke, Mailin C; Emschermann, Frederic; Rheinlaender, Johannes; von Eysmondt, Hendrik; Ferreirós, Nerea; Sudman, Jessica; Witte, Alexander; Pelzl, Lisann; Borst, Oliver; Geisler, Tobias; Rath, Dominik; Bakchoul, Tamam; Gawaz, Meinrad; Schäffer, Tilman E; Lämmerhofer, Michael; Chatterjee, Madhumita.
Afiliação
  • Cebo M; Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany.
  • Dittrich K; Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany.
  • Fu X; Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany.
  • Manke MC; Department of Cardiology and Angiology and.
  • Emschermann F; Deutsche Forschungsgemeinschaft (DFG) Heisenberg Group Thrombocardiology, University Hospital Tübingen, Tübingen, Germany.
  • Rheinlaender J; Department of Cardiology and Angiology and.
  • von Eysmondt H; Institute of Applied Physics, University of Tübingen, Tübingen, Germany.
  • Ferreirós N; Institute of Applied Physics, University of Tübingen, Tübingen, Germany.
  • Sudman J; Pharmazentrum Frankfurt, University Hospital Frankfurt, Frankfurt, Germany; and.
  • Witte A; Department of Cardiology and Angiology and.
  • Pelzl L; Department of Cardiology and Angiology and.
  • Borst O; Institute for Clinical and Experimental Transfusion Medicine (IKET), University Hospital Tübingen, Tübingen, Germany.
  • Geisler T; Department of Cardiology and Angiology and.
  • Rath D; Deutsche Forschungsgemeinschaft (DFG) Heisenberg Group Thrombocardiology, University Hospital Tübingen, Tübingen, Germany.
  • Bakchoul T; Department of Cardiology and Angiology and.
  • Gawaz M; Department of Cardiology and Angiology and.
  • Schäffer TE; Institute for Clinical and Experimental Transfusion Medicine (IKET), University Hospital Tübingen, Tübingen, Germany.
  • Lämmerhofer M; Department of Cardiology and Angiology and.
  • Chatterjee M; Institute of Applied Physics, University of Tübingen, Tübingen, Germany.
Blood ; 139(11): 1722-1742, 2022 03 17.
Article em En | MEDLINE | ID: mdl-34905596
Platelet ACKR3/CXCR7 surface expression is enhanced and influences prognosis in coronary artery disease (CAD) patients, who exhibit a distinct atherothrombotic platelet lipidome. Current investigation validates the potential of ACKR3/CXCR7 in regulating thromboinflammatory response through its impact on the platelet lipidome. CAD patients with enhanced platelet ACKR3/CXCR7 expression exhibited reduced aggregation. Pharmacological CXCR7 agonist (VUF11207) significantly reduced prothrombotic platelet response in blood from acute coronary syndrome patients ex vivo. CXCR7 agonist administration reduced thrombotic functions and thromboinflammatory plateletleukocyte interactions post-myocardial infarction and arterial injury in vivo. ACKR3/CXCR7 ligation did not affect surface availability of surface receptors, coagulation profile, bleeding time, plasma-dependent thrombin generation (thrombinoscopy), or clot formation (thromboelastography) but counteracted activation-induced phosphatidylserine exposure and procoagulant platelet-assisted thrombin generation. Targeted (micro-UHPLC-ESI-QTrap-MS/MS) and untargeted (UHPLCESI-QTOF-MS/MS) lipidomics analysis revealed that ACKR3/CXCR7 ligation favored generation of antithrombotic lipids (dihomo-γ-linolenic acid [DGLA], 12-hydroxyeicosatrienoic acid [12-HETrE]) over cyclooxygenase-1 (COX-1) or 12-lipoxygenase (12-LOX) metabolized prothrombotic and phospholipase-derived atherogenic lipids in healthy subjects and CAD patients, contrary to antiplatelet therapy. Through 12-HETrE, ACKR3/CXCR7 ligation coordinated with Gαs-coupled prostacyclin receptor to trigger cyclic adenosine monophosphate/protein kinase A-mediated platelet inhibition. ACKR3/CXCR7 ligation reduced generation of lipid agonists and lipid signaling intermediates, which affected calcium mobilization, intracellular signaling, and consequently platelet interaction with physiological matrices and thromboinflammatory secretome. This emphasized its functional dichotomy from prothrombotic CXCR4. Moreover, CXCR7 agonist regulated heparin-induced thrombocytopenia-sera/immunoglobulin G-triggered platelet and neutrophil activation, heparin-induced platelet aggregation, generation of thromboinflammatory lipids, platelet-neutrophil aggregate formation, and thromboinflammatory secretion ex vivo. Therefore, ACKR3/CXCR7 may offer a novel therapeutic strategy in acute/chronic thromboinflammation exaggerated cardiovascular pathologies and CAD.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Receptores CXCR Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Receptores CXCR Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article