Rivaroxaban Inhibits Angiotensin II-Induced Activation in Cultured Mouse Cardiac Fibroblasts Through the Modulation of NF-<i>κ</i>B Pathway
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- Hashikata Takehiro
- Kitasato University Graduate School of Medical Sciences
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- Yamaoka-Tojo Minako
- Kitasato University Graduate School of Medical Sciences Department of Rehabilitation, Kitasato University School of Allied Health Sciences
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- Namba Sayaka
- Kitasato University Graduate School of Medical Sciences
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- Kitasato Lisa
- Kitasato University Graduate School of Medical Sciences
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- Kameda Ryo
- Department of Cardiovascular Medicine, Kitasato University School of Medicine
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- Murakami Masami
- Department of Cardiovascular Medicine, Kitasato University School of Medicine
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- Niwano Hiroe
- Department of Education, Tamagawa University College of Education
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- Shimohama Takao
- Department of Cardiovascular Medicine, Kitasato University School of Medicine
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- Tojo Taiki
- Department of Cardiovascular Medicine, Kitasato University School of Medicine
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- Ako Junya
- Kitasato University Graduate School of Medical Sciences Department of Cardiovascular Medicine, Kitasato University School of Medicine
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説明
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.<br>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).<br>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.
収録刊行物
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- International Heart Journal
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International Heart Journal 56 (5), 544-550, 2015
一般社団法人 インターナショナル・ハート・ジャーナル刊行会