Abstract
Objective: We have reported that capillary degeneration in heart, observed in the early stage of pulmonary arterial hypertension (PAH), accelerates right ventricular (RV) remodeling in rats treated with Sugen5416 and chronic hypoxia. Recently, rivaroxaban, a specific factor Xa inhibitor in the coagulation cascade, was reported to have a pleiotropic effect of anti-inflammation. The aim of this study was to evaluate the preventive and therapeutic effects of rivaroxaban on vascular remodeling of heart and lung in vivo and in vitro.
Methods: Male Sprague-Dawley rats were exposed to hypoxia (10% O2) for 2 weeks after Sugen5416 subcutaneous injection (20 mg/kg, SU-hypoxia group). They were then returned to normoxia, and divided into 2 groups with/without rivaroxaban treatment (1.2 g rivaroxaban/kg chow) for additional 4 weeks. After hemodynamic evaluation, heart and lung were examined by microscopy, immunohistochemistry, RT-PCR, and Western blotting. Human cardiac microvascular endothelial cells (HCMEC) and pulmonary arterial endothelial cells (HPAEC) with/without rivaroxaban (1 μM) were cultured under hypoxic conditions (1% O2) in vitro.
Results: In SU-hypoxia group, degeneration of capillaries and cardiomyocytes in both atrial and ventricular myocardium were accelerated during 4 weeks observation, and increased wall thickness of lung muscular arteries was observed. Although rivaroxaban did not improve RV function (TAPSE 1.57 vs SU-hypoxia 1.45, Control 2.65), ultrastructure of capillaries and number of atrial specific granules were preserved by the treatment. And superoxide production and oxidative stress in the heart and lung were significantly suppressed by rivaroxaban. The increased expression of ERK1/2 and NF-kB mRNA caused by chronic hypoxia in heart and lung were significantly suppressed after the treatment with rivaroxaban. Furthermore, the increased expression of phosphorylated ERK1/2 and NF-kB caused by chronic hypoxia in HCMEC and HPAEC were significantly suppressed after the treatment with rivaroxaban.
Conclusion: Rivaroxaban attenuates vascular remodeling in PAH at least partly through anti-inflammatory and anti-oxidative effects related to the suppression of ERK1/2 and NF-kB phosphorylation, suggesting a novel therapeutic strategy in the treatment of PAH.
