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Activated Factor X Signaling Pathway via Protease-Activated Receptor 2 Is a Novel Therapeutic Target for Preventing Atrial Fibrillation
Circulation Journal ( IF 3.3 ) Pub Date : 2021-07-21 , DOI: 10.1253/circj.cj-20-1006
Tomomi Matsuura 1 , Takeshi Soeki 1, 2 , Daiju Fukuda 3 , Etsuko Uematsu 1 , Takeshi Tobiume 1 , Tomoya Hara 4 , Kenya Kusunose 1 , Takayuki Ise 1 , Koji Yamaguchi 1 , Shusuke Yagi 1 , Hirotsugu Yamada 1, 5 , Tetsuzo Wakatsuki 1 , Masataka Sata 1
Affiliation  

Background:Activated factor X (FXa), which contributes to chronic inflammation via protease-activated receptor 2 (PAR2), might play an important role in atrial fibrillation (AF) arrhythmogenesis. This study aimed to assess whether PAR2 signaling contributes to AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.

Methods and Results:In Study 1, PAR2 deficient (PAR2−/−) and wild-type mice were infused with angiotensin II (Ang II) or a vehicle via an osmotic minipump for 2 weeks. In Study 2, spontaneously hypertensive rats (SHRs) were treated with rivaroxaban, warfarin, or vehicle for 2 weeks after 8 h of right atrial rapid pacing. The AF inducibility and atrial remodeling in both studies were examined. Ang II-treated PAR2−/− mice had a lower incidence of AF and less mRNA expression of collagen1 and collagen3 in the atrium compared to wild-type mice treated with Ang II. Rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHRs treated with a vehicle, rapid atrial pacing promoted gene expression of inflammatory and fibrosis-related biomarkers in the atrium. Rivaroxaban, but not warfarin, significantly reduced expression levels of these genes.

Conclusions:The FXa–PAR2 signaling pathway might contribute to AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility, probably by inhibiting the pro-inflammatory activation.



中文翻译:

通过蛋白酶激活受体 2 的激活因子 X 信号通路是预防心房颤动的新型治疗靶点

背景:通过蛋白酶激活受体 2 (PAR2) 促成慢性炎症的活化因子 X (FXa) 可能在心房颤动 (AF) 心律失常发生中起重要作用。本研究旨在评估 PAR2 信号传导是否有助于 AF 心律失常发生,以及利伐沙班是否能改善心房炎症并预防 AF。

方法和结果:在研究 1 中,PAR2 缺陷型 (PAR2-/-) 和野生型小鼠通过渗透性微型泵注入血管紧张素 II (Ang II) 或载体 2 周。在研究 2 中,自发性高血压大鼠 (SHR) 在右心房快速起搏 8 小时后用利伐沙班、华法林或载体治疗 2 周。检查了两项研究中的 AF 诱导性和心房重构。与用 Ang II 治疗的野生型小鼠相比,Ang II 治疗的 PAR2-/- 小鼠的 AF 发生率较低,心房中胶原蛋白 1 和胶原蛋白 3 的 mRNA 表达较少。与华法林或赋形剂相比,利伐沙班显着降低了 AF 诱导率。在用载体治疗的 SHR 中,快速心房起搏促进了心房中炎症和纤维化相关生物标志物的基因表达。利伐沙班,但不是华法林,显着降低了这些基因的表达水平。

结论: FXa-PAR2 信号通路可能有助于与心房炎症相关的 AF 心律失常发生。直接 FXa 抑制剂利伐沙班可能通过抑制促炎激活来预防心房炎症并降低 AF 诱导率。

更新日期:2021-07-20
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