Abstract Number: PB0171
Meeting: ISTH 2020 Congress
Background: Atrial fibrillation (AF) is associated with a hypercoagulable state. Activation of protease-activated receptors (PAR) by thrombin mediates pro-fibrotic and pro-inflammatory responses in adult atrial fibroblasts which may support AF progression. Although factor (F) Xa is also known to activate PARs, its contribution to cardiac remodeling during AF remains unclear.
Aims: To elucidate the effect of thrombin and FXa on cardiac fibroblasts and clarify the role of PAR activation in cardiac remodeling during AF.
Methods: Primary adult rat cardiac fibroblasts were incubated with thrombin (0.01 U/mL) and FXa (100 nM). Gene expression of α-smooth muscle actin (α-SMA), Transforming growth factor-β1 (TGF-β1), Interleukin-6 (IL-6), Monocyte chemoattractant protein 1 (MCP-1) and PAR were determined after 4, and 24 hours. The expression of PAR-1 and PAR-2 was inhibited by siRNA.
Results: Thrombin and FXa increased cardiac fibroblast mRNA expression of α-SMA (24h: 3 and 2.5-fold respectively, p< 0.05; n=8) and TGF-β1 (4h: 2-fold, p< 0.05; n=8). PAR-1 silencing tended to inhibit this upregulation.
Thrombin and FXa induced a fast upregulation of IL-6 (4h: 2 and 6-fold respectively, 24h: 3-fold by FXa, p< 0.05; n=8) and MCP-1 (4h: 7 and > 10-fold respectively, 24: > 10-fold by FXa, p< 0.05; n=8).
PAR-1 silencing prevented the upregulation of MCP-1 induced by thrombin at 4h. However, neither PAR-1 nor PAR-2 knockdown reduced the upregulation of MCP-1 induced by FXa (n=8).
Conclusions: The upregulation of α-SMA and TGF-β1 triggered by thrombin and FXa in cardiac fibroblasts, suggests that these proteases may play a role in cardiac fibrosis during AF.
Both stimuli increased IL-6 and MCP-1 expression highlighting a pro-inflammatory stimulation in this cell type. Surprisingly, PAR-silencing downregulated the effect of thrombin but not the effect of FXa on MCP-1 expression, suggesting that FXa might induce pro-inflammatory responses through a PAR-independent pathway.
To cite this abstract in AMA style:D'Alessandro E, Scaf B, Munts C, Verheule S, van Oerle R, Spronk H, ten Cate H, Schotten U, van Nieuwenhoven F. Factor Xa Stimulates PAR-Independent Pro-Inflammatory Responses in Primary Adult Rat Cardiac Fibroblasts [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/factor-xa-stimulates-par-independent-pro-inflammatory-responses-in-primary-adult-rat-cardiac-fibroblasts/. Accessed November 30, 2021.
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