title: Rivaroxaban Inhibits Angiotensin II-Induced Activation in Cultured Mouse Cardiac Fibroblasts Through the Modulation of NF-κB 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.
authors.affiliation: Kitasato University Graduate School of Medical Sciences.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Hashikata
authors.forename: Minako
authors.initials: M
authors.lastname: Yamaoka-Tojo
authors.forename: Sayaka
authors.initials: S
authors.lastname: Namba
authors.forename: Lisa
authors.initials: L
authors.lastname: Kitasato
authors.forename: Ryo
authors.initials: R
authors.lastname: Kameda
authors.forename: Masami
authors.initials: M
authors.lastname: Murakami
authors.forename: Hiroe
authors.initials: H
authors.lastname: Niwano
authors.forename: Takao
authors.initials: T
authors.lastname: Shimohama
authors.forename: Taiki
authors.initials: T
authors.lastname: Tojo
authors.forename: Junya
authors.initials: J
authors.lastname: Ako
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D065427:Factor Xa Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D044464:Receptor, PAR-2; D000069552:Rivaroxaban / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D065427:Factor Xa Inhibitors; D016328:NF-kappa B; D044464:Receptor, PAR-2; D000804:Angiotensin II; D000069552:Rivaroxaban