Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways
Background Factor Xa (FXa) not only plays an active role in the coagulation cascade but also exerts non-hemostatic signaling through the protease-activated receptors (PARs). This study aimed to investigate whether the FXa inhibitor, Rivaroxaban (RIV), attenuates adverse cardiac remodeling in rats wi...
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PeerJ Inc.
2023-09-01
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| Online Access: | https://peerj.com/articles/16097.pdf |
| _version_ | 1827601588824309760 |
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| author | Qian Zhang Zhongfan Zhang Weiwei Chen Haikuo Zheng Daoyuan Si Wenqi Zhang |
| author_facet | Qian Zhang Zhongfan Zhang Weiwei Chen Haikuo Zheng Daoyuan Si Wenqi Zhang |
| author_sort | Qian Zhang |
| collection | DOAJ |
| description | Background Factor Xa (FXa) not only plays an active role in the coagulation cascade but also exerts non-hemostatic signaling through the protease-activated receptors (PARs). This study aimed to investigate whether the FXa inhibitor, Rivaroxaban (RIV), attenuates adverse cardiac remodeling in rats with myocardial infarction (MI) and to identify the underlying molecular mechanisms it uses. Methods An MI model was induced in eight-week-old, male Wistar rats, by permanent ligation of the left anterior descending coronary artery. MI rats were randomly assigned to receive RIV or protease-activated receptors 2-antagonist (PAR-2 antagonist, FSLLRY) treatment for four weeks. Histological staining, echocardiography and hemodynamics were used to assess the cardioprotective effects of RIV. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe the potential pathways in which RIV exerts antifibrotic effects in neonatal rat cardiac fibroblasts (CFs). In addition, real-time PCR and western blot analysis were performed to examine the associated signaling pathways. Results RIV presented favorable protection of left ventricular (LV) cardiac function in MI rats by significantly reducing myocardial infarct size, ameliorating myocardial pathological damage and improving left ventricular (LV) remodeling. Similar improvements in the PAR-2 antagonist FSLLRY and RIV groups suggested that RIV protects against cardiac dysfunction in MI rats by ameliorating PAR-2 activation. Furthermore, an in vitro model of fibrosis was then generated by applying angiotensin II (Ang II) to neonatal rat cardiac fibroblasts (CFs). Consistent with the findings of the animal experiments, RIV and FSLLRY inhibited the expression of fibrosis markers and suppressed the intracellular upregulation of transforming growth factor β1 (TGFβ1), as well as its downstream Smad2/3 phosphorylation effectors in Ang II-induced fibrosis, and PAR-2 agonist peptide (PAR-2 AP) reversed the inhibition effect of RIV. Conclusions Our findings demonstrate that RIV attenuates MI-induced cardiac remodeling and improves heart function, partly by inhibiting the activation of the PAR-2 and TGF-β1 signaling pathways. |
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| language | English |
| last_indexed | 2024-03-09T05:00:40Z |
| publishDate | 2023-09-01 |
| publisher | PeerJ Inc. |
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| spelling | doaj.art-043f9dc94446458db323365acb089bf32023-12-03T12:59:43ZengPeerJ Inc.PeerJ2167-83592023-09-0111e1609710.7717/peerj.16097Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathwaysQian Zhang0Zhongfan Zhang1Weiwei Chen2Haikuo Zheng3Daoyuan Si4Wenqi Zhang5Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, ChinaDepartment of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, ChinaDepartment of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, ChinaDepartment of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, ChinaDepartment of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, ChinaDepartment of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, ChinaBackground Factor Xa (FXa) not only plays an active role in the coagulation cascade but also exerts non-hemostatic signaling through the protease-activated receptors (PARs). This study aimed to investigate whether the FXa inhibitor, Rivaroxaban (RIV), attenuates adverse cardiac remodeling in rats with myocardial infarction (MI) and to identify the underlying molecular mechanisms it uses. Methods An MI model was induced in eight-week-old, male Wistar rats, by permanent ligation of the left anterior descending coronary artery. MI rats were randomly assigned to receive RIV or protease-activated receptors 2-antagonist (PAR-2 antagonist, FSLLRY) treatment for four weeks. Histological staining, echocardiography and hemodynamics were used to assess the cardioprotective effects of RIV. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe the potential pathways in which RIV exerts antifibrotic effects in neonatal rat cardiac fibroblasts (CFs). In addition, real-time PCR and western blot analysis were performed to examine the associated signaling pathways. Results RIV presented favorable protection of left ventricular (LV) cardiac function in MI rats by significantly reducing myocardial infarct size, ameliorating myocardial pathological damage and improving left ventricular (LV) remodeling. Similar improvements in the PAR-2 antagonist FSLLRY and RIV groups suggested that RIV protects against cardiac dysfunction in MI rats by ameliorating PAR-2 activation. Furthermore, an in vitro model of fibrosis was then generated by applying angiotensin II (Ang II) to neonatal rat cardiac fibroblasts (CFs). Consistent with the findings of the animal experiments, RIV and FSLLRY inhibited the expression of fibrosis markers and suppressed the intracellular upregulation of transforming growth factor β1 (TGFβ1), as well as its downstream Smad2/3 phosphorylation effectors in Ang II-induced fibrosis, and PAR-2 agonist peptide (PAR-2 AP) reversed the inhibition effect of RIV. Conclusions Our findings demonstrate that RIV attenuates MI-induced cardiac remodeling and improves heart function, partly by inhibiting the activation of the PAR-2 and TGF-β1 signaling pathways.https://peerj.com/articles/16097.pdfRivaroxabanCoagulation factor XaAdverse cardiac remodelingProtease-activated receptors-2Transforming growth factor β1 (TGFβ1) |
| spellingShingle | Qian Zhang Zhongfan Zhang Weiwei Chen Haikuo Zheng Daoyuan Si Wenqi Zhang Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways PeerJ Rivaroxaban Coagulation factor Xa Adverse cardiac remodeling Protease-activated receptors-2 Transforming growth factor β1 (TGFβ1) |
| title | Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways |
| title_full | Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways |
| title_fullStr | Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways |
| title_full_unstemmed | Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways |
| title_short | Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways |
| title_sort | rivaroxaban a direct inhibitor of coagulation factor xa attenuates adverse cardiac remodeling in rats by regulating the par 2 and tgf β1 signaling pathways |
| topic | Rivaroxaban Coagulation factor Xa Adverse cardiac remodeling Protease-activated receptors-2 Transforming growth factor β1 (TGFβ1) |
| url | https://peerj.com/articles/16097.pdf |
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