title: Platelets as a novel source of Gremlin-1: Implications for thromboinflammation.
abstract: Platelets mediating haemostasis-thrombosis are central players in coronary artery disease (CAD). We characterised platelets as a novel source of Gremlin-1. Platelets express Gremlin-1 like inflammatory and endothelial cells. Gremlin-1 co-localised with P-selectin containing randomly distributed α-granules under resting state, which were peripheralised following platelet activation or adhesion over fibrinogen-coated surface. Gremlin-1 release upon activation with ADP, CRP, and TRAP was detected as enhanced surface expression; also in activated platelet supernatant as detected by Western Blot following CRP activation and by ELISA upon activation with ADP, CRP, PAR-1, and PAR4 agonist. Recombinant (rh)Gremlin-1 synergistically enhanced CRP-triggered intracellular calcium mobilisation, ADP-TRAP induced platelet activation, aggregation, and thrombin-activation triggered apoptosis; also thrombus formation ex vivo. Intracellular localisation of macrophage migration inhibitory factor (MIF) and Gremlin-1 a high-affinity binding partner and functional antagonist of MIF were found in intracoronary thrombus sections from acute coronary syndrome (ACS) patients and showed moderate overlap in α-granules of platelets. Intra-platelet Gremlin-1 levels were significantly decreased in ACS patients as compared to stable CAD (n=235). rhGremlin-1 also counteracted the anti-apoptotic and anti-thrombotic effects of rhMIF on platelets. Platelet-derived-Gremlin-1 prompted monocyte migration, facilitated adhesion under static and dynamic arterial flow conditions to collagen-adherent activated platelets; supported monocyte survival against BH-3-mimetic-induced apoptosis and macrophage differentiation in monocyte-platelet co-culture system, which were counteracted upon Gremlin-1 neutralisation. Thus platelet derived Gremlin-1 might contribute to the elevated circulating levels of Gremlin-1 in ACS and serve as a thrombo-inflammatory mediator in cardiovascular pathophysiologies.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Alexander
authors.initials: A
authors.lastname: Behrendt
authors.forename: Martina
authors.initials: M
authors.lastname: Schmid
authors.forename: Sandra
authors.initials: S
authors.lastname: Beck
authors.forename: Martina
authors.initials: M
authors.lastname: Schneider
authors.forename: Andreas
authors.initials: A
authors.lastname: Mack
authors.forename: Iris
authors.initials: I
authors.lastname: Müller
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.affiliation: Meinrad Gawaz, MD, Innere Medizin III, Eberhard Karls Universität Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany, Tel.: + 49 7071 29 83688, Fax: + 49 7071 29 57 49, E-mail: meinrad.gawaz@med.uni-tuebingen.de.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood* / Q000473:pathology; D000368:Aged; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D019746:Intramolecular Oxidoreductases / Q000097:blood; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D015539:Platelet Activation / Q000187:drug effects; D011446:Prospective Studies; D011485:Protein Binding; D013927:Thrombosis / Q000097:blood* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: Gremlin-1; acute coronary syndrome; monocytes; platelets; thrombus