Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension
- 1 May 2021
- journal article
- research article
- Published by Pharmaceutical Society of Japan in Biological & Pharmaceutical Bulletin
- Vol. 44 (5), 669-677
- https://doi.org/10.1248/bpb.b20-01011
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.Keywords
This publication has 41 references indexed in Scilit:
- Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking ELTD1PLOS ONE, 2012
- Complement C3 Deficiency Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension in MicePLOS ONE, 2011
- Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean miceHypertension Research, 2010
- ERK and cell death: Mechanisms of ERK‐induced cell death – apoptosis, autophagy and senescenceThe FEBS Journal, 2009
- JNK signaling in apoptosisOncogene, 2008
- Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertensionAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2007
- Angiotensin II Receptor Blocker Reduces Oxidative Stress and Attenuates Hypoxia-Induced Left Ventricular Remodeling in Apolipoprotein E-Knockout MiceHypertension Research, 2007
- A role for proteinase-activated receptor 2 and PKC-ε in thrombin-mediated induction of decay-accelerating factor on human endothelial cellsAmerican Journal of Physiology-Cell Physiology, 2005
- The multi-targeted kinase inhibitor SU5416 inhibits small cell lung cancer growth and angiogenesis, in part by blocking Kit-mediated VEGF expressionLung Cancer, 2004
- Ultrastructure and immunohistochemistry of the coronary chemoreceptor in human and canine heartsAmerican Heart Journal, 1995