Author + information
- Rintaro Mitsuishi,
- Hideki Imano,
- Ryuji Kato,
- Yoshio Ijiri,
- Takehiro Yamaguchi,
- Minoru Yoshiyama and
- Tetsuya Hayashi
Background: The cumulative frequency of atrial fibrillation (AF) is high in patients with sleep apnea. We have reported that intermittent hypoxia (IH: repeated cycles of 1.5 minute of 5% oxygen followed by 5 minutes of 21% oxygen) 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 for 28 days with treatment by rivaroxaban (1.2 g riv./kg chow), PAR-1 antagonist (SCH 79797), or PAR-2 antagonist (FSLLRY). Human pulmonary artery endothelial cells (HPAECs) or human cardiac microvascular endothelial cells (HCMEC) were cultured under hypoxic conditions (1% O2) with/without rivaroxaban (1 µM).
Results: IH caused cardiomyocyte hypertrophy and increased perivascular fibrosis, associated with increased E/e’ (early rapid filling wave of mitral inflow velocities over early velocities of the mitral annulus), which were attenuated by rivaroxaban. In right atrial myocardium, IH caused endothelial cell degeneration and dissociation of intercalated discs, increased autophagosomes and autolysosomes, associated with increased ANP specific granules, and vacuolar formation. Furthermore, 4-hydroxy-2-nonenal protein adducts and the expression of PAR-1, PAR-2, ERK1/2 and NF-kB mRNA in the left ventricular myocardium were increased by IH. Treatment with rivaroxaban significantly suppressed PAR-1, PAR-2, ERK1/2 and NF-kB mRNA expression in vivo, reduced oxidative stress, occlusive capillaries, and degeneration of small arteries, preventing atrial as well as ventricular remodeling due to IH. In vitro study, the expression of PAR-1, PAR-2, ERK-1/2, and NF-κB mRNA were down-regulated by rivaroxaban.
Conclusions: Rivaroxaban attenuates cardiac remodeling induced by IH at least partly through the effects associated with PAR-1 and PAR-2.
Moderated Poster Contributions
Vascular Medicine Moderated Poster Theater, Poster Hall, Hall C
Sunday, March 19, 2017, 1:15 p.m.-1:25 p.m.
Session Title: Mechanisms of Vascular Inflammation in Atherogenesis
Abstract Category: 38. Vascular Medicine: Basic
Presentation Number: 1320M-09
- 2017 American College of Cardiology Foundation