Activated Factor X Signaling Pathway via Protease-Activated Receptor 2 Is a Novel Therapeutic Target for Preventing Atrial Fibrillation

• Published in: Circulation Journal Vol. 85; no. 8; pp. 1383 - 1391
• Main Authors: Matsuura, Tomomi, Soeki, Takeshi, Fukuda, Daiju, Uematsu, Etsuko, Tobiume, Takeshi, Hara, Tomoya, Kusunose, Kenya, Ise, Takayuki, Yamaguchi, Koji, Yagi, Shusuke, Yamada, Hirotsugu, Wakatsuki, Tetsuzo, Sata, Masataka
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 21-07-2021
• Subjects: Angiotensin II; Animals; Anticoagulants; Atrial fibrillation; Atrial Fibrillation - drug therapy; Atrial Fibrillation - prevention & control; Factor Xa; Inflammation; Mice; PAR2; Rats; Receptor, PAR-2 - genetics; Rivaroxaban - pharmacology; Signal Transduction; Warfarin; Anticoagulants; Inflammation; PAR2; Atrial fibrillation
• ISSN: 1346-9843; 1347-4820; 1347-4820
• DOI: 10.1253/circj.CJ-20-1006

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.