1. Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension
- Author
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Hong Wu, Minoru Yoshiyama, Yoshikatsu Okada, Yasukatsu Izumi, Takehiro Yamaguchi, Yoshio Ijiri, Hideki Imano, Atsuo Nomura, Yudai Yamaguchi, Takashi Nakano, Ryuji Kato, Tetsuya Hayashi, Maki Tamura, and Michio Asahi
- Subjects
Male ,0301 basic medicine ,MAPK/ERK pathway ,Indoles ,Heart Ventricles ,Cell Culture Techniques ,Pharmaceutical Science ,Blood Pressure ,Pharmacology ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Rivaroxaban ,Extracellular ,Animals ,Humans ,Medicine ,Pyrroles ,Extracellular Signal-Regulated MAP Kinases ,Hypoxia ,Ventricular remodeling ,Pulmonary Arterial Hypertension ,Ventricular Remodeling ,business.industry ,Kinase ,JNK Mitogen-Activated Protein Kinases ,NF-kappa B ,Endothelial Cells ,General Medicine ,Hypoxia (medical) ,medicine.disease ,In vitro ,Disease Models, Animal ,030104 developmental biology ,Blood pressure ,030220 oncology & carcinogenesis ,medicine.symptom ,business ,Factor Xa Inhibitors ,medicine.drug - Abstract
Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (1.2 mg/kg/day) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37°C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.
- Published
- 2021