Pham, Tran Phuong Tokushima University
Kusunose, Kenya Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Yamada, Hirotsugu Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Soeki, Takeshi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Sata, Masataka Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Thesis or Dissertation
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.
本論文は，著者Phuong Tran Phamの学位論文として提出され，学位審査・授与の対象となっている
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k3432_abstract_review.pdf 195 KB
k3432_fulltext.pdf 1.64 MB
|MEXT report number||
Doctor of Medical Science