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Factor Xa inhibition by rivaroxaban attenuates cardiac remodeling due to intermittent hypoxia
- Source :
- Journal of Pharmacological Sciences. 137:274-282
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Patients with obstructive sleep apnea (OSA) have a high prevalence of atrial fibrillation (AF). Rivaroxaban, a coagulation factor Xa inhibitor, has recently been reported to show pleiotropic effects. This study investigated the influence of rivaroxaban on cardiac remodeling caused by intermittent hypoxia (IH). Male C57BL/6J mice were exposed to IH (repeated cycles of 5% oxygen for 1.5 min followed by 21% oxygen for 5 min) for 28 days with/without rivaroxaban (12 mg/kg/day) or FSLLRY, a protease-activated receptor (PAR)-2 antagonist (10 μg/kg/day). IH caused endothelial cell degeneration in the small arteries of the right atrial myocardium and increased the level of %fibrosis and 4-hydroxy-2-nonenal protein adducts in the left ventricular myocardium. IH also increased the expression of PAR-2 as well as the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and nuclear factor-kappa B (NF-κB) were increased in human cardiac microvascular endothelial cells. However, rivaroxaban and FSLLRY significantly suppressed these changes. These findings demonstrate that rivaroxaban attenuates both atrial and ventricular remodeling induced by IH through the prevention of oxidative stress and fibrosis by suppressing the activation of ERK and NF-κB pathways via PAR-2. Treatment with rivaroxaban could potentially become a novel therapeutic strategy for cardiac remodeling in patients with OSA and AF.
- Subjects :
- Male
0301 basic medicine
MAPK/ERK pathway
MAP Kinase Signaling System
030204 cardiovascular system & hematology
Pharmacology
medicine.disease_cause
03 medical and health sciences
0302 clinical medicine
Rivaroxaban
Fibrosis
Atrial Fibrillation
medicine
Animals
Receptor, PAR-2
Molecular Targeted Therapy
Hypoxia
Ventricular remodeling
Cells, Cultured
Sleep Apnea, Obstructive
Ventricular Remodeling
business.industry
Myocardium
NF-kappa B
Endothelial Cells
Atrial fibrillation
Intermittent hypoxia
medicine.disease
Mice, Inbred C57BL
Endothelial stem cell
Oxidative Stress
030104 developmental biology
Molecular Medicine
business
Oligopeptides
Oxidative stress
Factor Xa Inhibitors
medicine.drug
Subjects
Details
- ISSN :
- 13478613
- Volume :
- 137
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacological Sciences
- Accession number :
- edsair.doi.dedup.....b20aad0775c463ae37c0c1581ddd5d18
- Full Text :
- https://doi.org/10.1016/j.jphs.2018.07.002