Abstract 18663: Rivaroxaban, but Not PAR-2 Antagonist, Attenuates Cardiac Remodeling Due to Intermittent Hypoxia in Sleep Apnea Model Mice
Introduction: The cumulative frequency of atrial fibrillation (AF) is high in patients with sleep apnea. We have reported that intermittent hypoxia (IH) relevant to sleep apnea increases oxidative stress causing vascular remodeling. Recently, pleiotropic effects of serine protease factor Xa (FXa) have been reported. The aim of study was to investigate the effect of FXa inhibitor rivaroxaban on atrial and ventricular remodeling caused by IH relevant to sleep apnea in vivo and in vitro.
Methods: Male C57BL/6J mice were exposed to IH (repeated cycles of 1.5 min of 5% oxygen followed by 5 min of 21% oxygen) for 28 days with/without treatment by rivaroxaban (1.2 g riv./kg chow) or protease-activated receptor (PAR)-2 antagonist (FSLLRY-NH2, 10 μg/kg/day). Human pulmonary artery endothelial cells were cultured under hypoxic conditions (1% oxygen for 24 hr) with/without rivaroxaban (1 μM) or FSLLRY-NH2 (10μM).
Results: IH caused cardiac remodeling, associated with both systolic and diastolic dysfunction (IH-vehicle vs. Normoxia; EF: 51% vs. 60% and E/e’: 29.4 vs. 22.3), which were attenuated by rivaroxaban (EF:56%, E/e’ 24.6), but not by FSLLRY (EF: 52%, E/e’: 25.1). In right atrial myocardium, IH caused endothelial cell degeneration, dissociation of intercalated discs, vacuolar formation and loss of ANP specific granules. Furthermore, 4-hydroxy-2-nonenal protein adducts and the expressions of PAR-2, ERK1/2 and NF-kB mRNA in the left ventricular myocardium were increased by IH. Treatment with rivaroxaban significantly suppressed PAR-2, ERK1/2 and NF-kB mRNA expressions in vitro, reduced oxidative stress and degeneration of small arteries, but not observed in treatment with the PAR-2 antagonist, preventing atrial as well as ventricular remodeling due to IH.
Conclusions: Both rivaroxaban and FSLLRY-NH2 exert anti-inflammatory effects via the PAR-2/ERK/NF-κB signaling pathway. Rivaroxaban, but not PAR-2 antagonist, reduces oxidative stress and attenuates capillary endothelial cell degeneration and thrombosis induced by IH in atrial appendage, which might be a novel therapeutic strategy by FXa inhibition against atrial remodeling in patients with AF.
Author Disclosures: S. Morita: None. A. Fujiwara: None. T. Kondo: None. K. Fujii: None. H. Imano: None. R. Kato: None. Y. Ijiri: None. T. Yamaguchi: None. Y. Izumi: None. M. Yoshiyama: None. T. Hayashi: None.
- © 2016 by American Heart Association, Inc.