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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 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Administration of rivaroxaban (10\u2009mg\/kg\/day) to diabetic wild-type (WT) mice for 3 weeks attenuated endothelial dysfunction as determined by acetylcholine-dependent vasodilation compared with the control (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), without alteration of blood glucose level. Rivaroxaban promoted eNOS<jats:sup>Ser1177<\/jats:sup>phosphorylation in the aorta (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). Induction of diabetes to PAR2-deficient (PAR2<jats:sup>\u2212\/\u2212<\/jats:sup>) mice did not affect endothelial function and eNOS<jats:sup>Ser1177<\/jats:sup>phosphorylation in the aorta compared with non-diabetic PAR2<jats:sup>\u2212\/\u2212<\/jats:sup>mice. FXa or a PAR2 agonist significantly impaired endothelial function in aortic rings obtained from WT mice, but not in those from PAR2<jats:sup>\u2212\/\u2212<\/jats:sup>mice. FXa promoted JNK phosphorylation (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01) and reduced eNOS<jats:sup>Ser1177<\/jats:sup>phosphorylation (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) and eNOS<jats:sup>Ser1177<\/jats:sup>phosphorylation (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) 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.<\/jats:p>","DOI":"10.1038\/s41598-019-47474-0","type":"journal-article","created":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T10:02:43Z","timestamp":1564653763000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Rivaroxaban, a specific FXa inhibitor, improved endothelium-dependent relaxation of aortic segments in diabetic mice"],"prefix":"10.1038","volume":"9","author":[{"given":"Phuong Tran","family":"Pham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiju","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusuke","family":"Yagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenya","family":"Kusunose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotsugu","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Soeki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7835-7665","authenticated-orcid":false,"given":"Michio","family":"Shimabukuro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Sata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,1]]},"reference":[{"key":"47474_CR1","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1046\/j.1538-7836.2003.00363.x","volume":"1","author":"EB Bachli","year":"2003","unstructured":"Bachli, E. 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