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

Tomomi Matsuura1, Takeshi Soeki1,2, Daiju Fukuda3

  • 1Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences.

Circulation Journal : Official Journal of the Japanese Circulation Society
|March 22, 2021
PubMed
Abstract

Insights

The factor Xa (FXa)-protease-activated receptor 2 (PAR2) pathway promotes atrial fibrillation (AF) and inflammation. Rivaroxaban, an FXa inhibitor, reduces AF inducibility and atrial inflammation, suggesting a therapeutic role.

Area of Science:

  • Cardiology
  • Pharmacology
  • Molecular Biology

Background:

  • Activated factor X (FXa) contributes to chronic inflammation via protease-activated receptor 2 (PAR2).
  • FXa-PAR2 signaling may play a role in atrial fibrillation (AF) arrhythmogenesis.

Purpose of the Study:

  • To investigate the contribution of PAR2 signaling to AF arrhythmogenesis.
  • To determine if rivaroxaban ameliorates atrial inflammation and prevents AF.

Main Methods:

  • Study 1: PAR2 deficient and wild-type mice infused with angiotensin II (Ang II) or vehicle.
  • Study 2: Spontaneously hypertensive rats (SHRs) treated with rivaroxaban, warfarin, or vehicle after rapid atrial pacing.
  • Assessment of AF inducibility and atrial remodeling.

Main Results:

  • PAR2 deficient mice showed lower AF incidence and atrial fibrosis markers after Ang II infusion.
  • Rivaroxaban significantly reduced AF inducibility in SHRs compared to warfarin or vehicle.
  • Rivaroxaban, unlike warfarin, reduced atrial inflammatory and fibrosis-related gene expression.

Conclusions:

  • The FXa-PAR2 pathway contributes to AF arrhythmogenesis and atrial inflammation.
  • Rivaroxaban may prevent AF by inhibiting pro-inflammatory activation and reducing atrial inflammation.
Keywords:
AnticoagulantsAtrial fibrillationInflammationPAR2

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