Factor Xa in Mouse Fibroblasts May Induce Fibrosis More Than Thrombin

Kitasato, Lisa; Yamaoka‐Tojo, Minako; Hashikata, Takehiro; Ishii, Shuji; Kameda, Ryo; Shimohama, Takao; Tojo, Taiki; Ako, Junya

doi:10.1536/ihj.13-351

Cited by 23 publications

(17 citation statements)

References 24 publications

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“…We have previously reported that the activation of cardiac fibroblasts is stimulated by FXa signaling via AP-1 and NF-κB pathways, accompanied by increasing ROS production and fibrotic signal activation through the ERK and JNK pathways. 14) Substances such as ROS are capable of activating intracellular transcription factors such as AP-1 and NF-κB. The MAPK/ ERK pathways also activate AP-1 and NF-κB, eventually inducing TIMP-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…13) Previous experiments in our laboratory demonstrated that the activation of fibroblast cardiac fibrosis is stimulated by FXa signaling via activator protein (AP)-1 and the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, accompanied by reactive oxygen species (ROS) elevation and fibrotic signal activation in growth-arrested fibroblasts. 14) Factor Xa (FXa) inhibitors are anticoagulants to prevent and treat stroke and other thromboembolic events. Rivaroxaban, an approved oral direct FXa inhibitor, has been evaluated in a number of clinical settings to prevent and treat venous thromboembolism and stroke prophylaxis in atrial fibrillation (AF).…”

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confidence: 99%

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

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2015

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“…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.…”

Section: Effect Of Rivaroxaban In the Non-infarcted Myocardiummentioning

confidence: 57%

“…[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.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding this point, previous studies using cultured and stimulated macrophages, fibroblasts and cardiomyocytes have already described the anti-inflammatory and antifibrotic effects of rivaroxaban. 16,34,43,44 We speculated that rivaroxaban might suppress the activation of these cells and regulate the inflammatory and fibrotic response in the infarcted lesions post-MI.…”

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confidence: 99%

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

et al. 2020

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It has been reported that combination therapies that include low-dose rivaroxaban seem to be effective in secondary prevention of acute coronary syndrome, 11 which suggests that rivaroxaban is effective not only for atrial fibrillation and venous thrombosis but also for coronary artery thrombosis. However, there is insufficient evidence about the cardioprotective effects of rivaroxaban on cardiac remodeling after MI. Rivaroxaban also exhibits anti-inflammatory properties, acting through amelioration of protease-activated receptor (PAR)-1 and-2 in arteriosclerosis models. 12-17 In addition, basic in vivo and in vitro research work has examined in detail the relationship between PARs and cardiac remod-C ardiac remodeling is an important prognostic factor in heart failure (HF). 1 Myocardial infarction (MI) is the most common cause of HF 2 and our understanding of the effect of cardiac remodeling in HF is based on MI studies. 3 The pathology of MI suggests that the inflammatory changes in the infarcted tissue correlate closely with cardiac function and prognosis after MI. 4,5 These findings suggest that modulation of the inflammatory response in the infarcted myocardium could potentially improve cardiac remodeling after MI. Rivaroxaban, an oral anticoagulant, is used to prevent and treat atrial fibrillation and venous thrombosis, because it exerts its anticoagulant properties by inhibiting activated

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Anti-inflammatory effect of factor-Xa inhibitors in Japanese patients with atrial fibrillation

2017

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Activated factor-X (FXa) plays an important role not only in the coagulation cascade, but also in pro-inflammatory responses. However, few data exist regarding the anti-inflammatory effect of FXa inhibitors in clinical practice. The aim of this study was to evaluate the anti-inflammatory and anti-atherosclerotic effects of FXa inhibitors in Japanese patients with non-valvular atrial fibrillation (NVAF). Eighty-three patients with NVAF were treated with FXa inhibitors from March 2013 to March 2015 at our institution. Of these, 55 patients who were not pretreated with warfarin or dabigatran (rivarixaban in 23 patients and apixaban in 32) were included in this study. We measured various inflammatory and coagulation markers at baseline and at 6 months after treatment. Plasma concentrations of pentraxin 3 (PTX3) (from 2.45 ± 1.31 to 1.97 ± 1.00 ng/mL, p = 0.0009) and fibrin and fibrinogen degradation products (FDP) D-dimer (from 1.18 ± 0.70 to 0.74 ± 0.32 μg/mL, p < 0.0001) decreased, while those of TM (from 2.9 ± 0.8 to 3.2 ± 0.9 FU/mL, p = 0.003) increased significantly at 6 months. Interestingly, change of each marker denoted the same tendency in both rivaroxaban and apixaban. In conclusion, the present study suggests that FXa inhibitors have not only an anti-coagulant effect but also anti-inflammatory effects in patients with NVAF. Further large-scale prospective study is necessary to evaluate whether changes in these markers will be associated with a lower risk for future cardiovascular events.

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Factor Xa in Mouse Fibroblasts May Induce Fibrosis More Than Thrombin

Cited by 23 publications

References 24 publications

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

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

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

Anti-inflammatory effect of factor-Xa inhibitors in Japanese patients with atrial fibrillation

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