Rivaroxaban Inhibits Angiotensin II-Induced Activation in Cultured Mouse Cardiac Fibroblasts Through the Modulation of NF-<i>κ</i>B Pathway

Abstract

Cell migration, proliferation, and differentiation of cardiac fibroblasts (CFs) play a central role in cardiac fibrosis. Factor Xa (FXa)-dependent protease-activated receptor (PAR)-1 and PAR-2 have been reported as important targets in proinflammatory and fibroproliferative diseases. From this viewpoint, we aimed to investigate whether treatment of rivaroxaban, an approved oral direct FXa inhibitor, attenuates functional changes in angiotensin (Ang) II-induced mouse CFs.Confluent cultured mouse CFs were pretreated with or without rivaroxaban. Ang II-induced cell migration was decreased by 73% in rivaroxaban induced cells. Rivaroxaban inhibited Ang II-induced cell proliferation by 27% at 0.01 μg/ mL, 69% at 0.1 μg/mL, 71% at 1 μg/mL, and 69% at 5 μg/mL. In mouse cytokine array measuring 40 cytokines, the productions of interleukin-16, TIMP-1, and tumor necrosis factor-α (TNF-α) were significantly reduced with 0.1 μg/mL of rivaroxaban pretreatment (all P < 0.05). TIMP-1 levels in the culture supernatant measured by ELISA were also decreased by rivaroxaban pretreatment in Ang II-induced CFs (35% decrease at 0.01 μg/mL, 47% at 0.1 μg/mL, 47% at 1 μg/mL, and 57% at 5 μg/mL). In the dual reporter assay analysis, rivaroxaban inhibited various inflammatory signal pathways, including the nuclear factor-kappa B (NF-κB), active protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) pathways (decreases of 82%, 78%, and 75%, respectively).These data suggest that rivaroxaban inhibits Ang II-induced functional activation in cultured mouse CFs via inhibiting NF-κB and MAPK/AP-1 signaling pathways, which may be a possible target of heart failure, through the antifibrotic and anti-inflammatory efficacy of rivaroxaban in Ang II-stimulated cardiac fibroblasts.

Ubiquitin Carboxyl Terminal Hydrolase L1 Attenuates TNF-α-Mediated Vascular Smooth Muscle Cell Migration Through Suppression of NF-κB Activation

“…29,30) Previous studies have demonstrated that TNF-α is a potent promoting migration factor for different cell types, including fibroblasts, inflammatory, and VSMCs. [31][32][33] In the present study, TNF-α could induce VSMC migration in a concentrationdependent manner from 0 to 10 ng/mL and with maximal activity at 10 ng/mL. According to a previous report, 34) 10 ng/mL of TNF-α showed no effect on VSMC proliferation when treated for 18 hours.…”

Cardioprotective Effects of Rivaroxaban on Cardiac Remodeling After Experimental Myocardial Infarction in Mice

“…The results demonstrated significant decreases in p-ERK in the non-infarcted have shown that stimulated macrophages, fibroblasts and cardiomyocytes express PAR-1 and PAR-2, and that rivaroxaban inhibited the activation of these cells through the suppression of PAR-1 and PAR-2. 16,34,43,44,47 It is possible that rivaroxaban could downregulate the activation of inflammatory cells and ischemic cardiomyocytes in the infarcted area by reducing the levels of PAR-1 and PAR-2, and then improve cardiac remodeling after MI, even though the numbers of inflammatory cells in the infarcted area were identical between the 2 treatment groups in the present study.…”

“…[35][36][37][38][39][40][41][42] Hara et al reported that stimulation of mice macrophages with FXa resulted in increases in inflammatory cytokines, and such increase was suppressed by rivaroxaban administration. 16 Other groups have demonstrated that rivaroxaban inhibits angiotensin II-induced functional activation in cultured cardiac fibroblasts, 43,44 and that rivaroxaban reduced the number of apoptotic cardiomyocytes and decreased the mRNA expression of proinflammatory cytokines. 34 In the present study, rivaroxaban interestingly reduced both TNF-α and TGF-β mRNA levels in the infarcted area.…”

Tripartite Motif Protein 72 Regulates the Proliferation and Migration of Rat Cardiac Fibroblasts via the Transforming Growth Factor-β Signaling Pathway

“…The Toll/Il-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) may promote atrial fibrosis via microphages [36][37][38] . Rivaroxaban has been reported to inhibit AngII-stimulated cardiac fibrosis through nuclear factor-κB and the mitogen-activated protein kinase pathway [39][40][41] . To the best of our knowledge, the present study has, for the first time, shown that Trim72 can regulate the migration of cardiac fibroblasts.…”