Rivaroxaban, a specific FXa inhibitor, improved endothelium-dependent relaxation of aortic segments in diabetic mice

• Material Type: 博士論文
• Title: Rivaroxaban, a specific FXa inhibitor, improved endothelium-dependent relaxation of aortic segments in diabetic mice
• Author/Editor: Pham, Tran Phuong; Fukuda, Daiju; Yagi, Shusuke; Kusunose, Kenya; Yamada, Hirotsugu; Soeki, Takeshi; Shimabukuro, Michio; Sata, Masataka
• Author Heading: Pham, Tran Phuong; Fukuda, Daiju; Yagi, Shusuke; Kusunose, Kenya; Yamada, Hirotsugu; Soeki, Takeshi; Shimabukuro, Michio; Sata, Masataka
• Publication, Distribution, etc.: Springer Nature
• Publication Date: 2019-08-01
• Publication Date (W3CDTF): 2019-08-01
• Alternative Title: 特異的活性化第X因子阻害薬であるリバーロキサバンは、糖尿病マウス大動脈の血管内皮依存性弛緩反応を改善した
• Periodical title: Scientific Reports
• No. or year of volume/issue: 9
• Volume: 9
• Pages: 11206-
• ISSN (Periodical Title): ISSN : 2045-2322
• Degree grantor/type: 徳島大学
• Date Granted: 2020-09-10
• Dissertation Number: 甲第3432号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Rivaroxaban; FXa; PAR2; Endothelial dysfunction
• Target Audience: 一般
• Note (General): Activated factor X (FXa) plays a central role in the coagulation cascade, while it also mediates vascular function through activation of protease-activated receptors (PARs). Here, we examined whether inhibition of FXa by rivaroxaban, a direct FXa inhibitor, attenuates endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Induction of diabetes increased the expression of a major FXa receptor, PAR2, in the aorta (P < 0.05). Administration of rivaroxaban (10 mg/kg/day) to diabetic wild-type (WT) mice for 3 weeks attenuated endothelial dysfunction as determined by acetylcholine-dependent vasodilation compared with the control (P < 0.001), without alteration of blood glucose level. Rivaroxaban promoted eNOSSer1177 phosphorylation in the aorta (P < 0.001). Induction of diabetes to PAR2-deficient (PAR2−/−) mice did not affect endothelial function and eNOSSer1177 phosphorylation in the aorta compared with non-diabetic PAR2−/− mice. FXa or a PAR2 agonist significantly impaired endothelial function in aortic rings obtained from WT mice, but not in those from PAR2−/− mice. FXa promoted JNK phosphorylation (P < 0.01) and reduced eNOSSer1177 phosphorylation (P < 0.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings (P < 0.001) and eNOSSer1177 phosphorylation (P < 0.05) in HCAEC were partially ameliorated by a JNK inhibitor. Rivaroxaban ameliorated diabetes-induced endothelial dysfunction. Our results suggest that FXa or PAR2 is a potential therapeutic target.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• Related Material (DOI): 10.1038/s41598-019-47474-0
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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