title: Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue.
abstract: Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, which is activated during atrial fibrillation. Increasing evidence suggests that FXa influences cell signalling in various cell types by activating protease-activated receptors (PARs). It is so far not known if molecular effects of FXa affect atrial signal transduction. To study the effects of FXa, human atrial tissue slices were cultivated with FXa up to 24h. Additionally, rapid pacing was applied at 4Hz to resemble atrial fibrillation. The inhibitory impact of FXa antagonist (Rivaroxaban), protease-activated receptor 1 antagonist (SCH79797), and protease-activated receptor 2 antagonist (GB83) were analysed under experimental conditions. The exposure of atrial tissue to FXa resulted in the 1.7 fold upregulation of PAR2-mRNA, activation of MAP kinases (ERK1/2) and NF-κB signalling. Furthermore FXa increased the expression of adhesion molecule ICAM-1 (1.82 ± 0.20), chemokine IL-8 (1.94 ± 0.20), as well as prothrombotic molecule PAI-1 (1.52 ± 0.17). The combination of rapid pacing and FXa caused significant upregulation of PAR1 (2.82 ± 0.22), PAR2 (2.66 ± 0.40), ICAM-1 (2.13 ± 0.25), IL-8 (2.22 ± 0.24), LOX-1 (2.59 ± 0.35), and PAI-1 (2.65 ± 0.52) at the mRNA level. Rivaroxaban and GB83 prevented upregulation of PARs, ICAM-1, LOX-1, IL-8, and activation of MAP kinases. The elevation in the expression of PAI-1 was hindered in the presence of SCH79797, or Rivaroxaban. The present study indicates that FXa mediates inflammatory signalling in atrial tissue. Importantly, FXa and tachyarrhythmia act synergistically to increase expression of protease-activated receptors and inflammatory mediators. Rivaroxaban prevented effectively FXa-induced molecular effects in human atrial tissue particularly during rapid pacing.
authors.affiliation: Working Group of Molecular Electrophysiology, Medical Faculty, Otto von Guericke University Magdeburg, Germany.
authors.forename: Alicja
authors.initials: A
authors.lastname: Bukowska
authors.forename: Ines
authors.initials: I
authors.lastname: Zacharias
authors.forename: Sönke
authors.initials: S
authors.lastname: Weinert
authors.forename: Kerstin
authors.initials: K
authors.lastname: Skopp
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Christof
authors.initials: C
authors.lastname: Huth
authors.forename: Andreas
authors.initials: A
authors.lastname: Goette
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000378:metabolism / Q000473:pathology; D064752:Atrial Remodeling / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015951:Factor Xa / Q000494:pharmacology*; D005260:Female; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014022:Tissue Survival / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D044462:Receptors, Proteinase-Activated; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015951:Factor Xa
keywords: Atrial fibrillation; FXa antagonist; FXa-induced signal transduction; PAR1 antagonist; PAR2 antagonist