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

• Published in: Scientific reports Vol. 9; no. 1; pp. 11206 - 11
• Main Authors: Pham, Phuong Tran, Fukuda, Daiju, Yagi, Shusuke, Kusunose, Kenya, Yamada, Hirotsugu, Soeki, Takeshi, Shimabukuro, Michio, Sata, Masataka
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2019; Nature Publishing Group
• Subjects: 64/60; 692/163/2743/137/138; 692/308/1426; 692/4019/592/75/593; 82/80; Acetylcholine; Animals; Anthracenes - pharmacology; Aorta; Aorta - drug effects; Aorta - physiopathology; Cell Line; Coagulation factors; Coronary artery; Coronary vessels; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetic Angiopathies - drug therapy; Diabetic Angiopathies - etiology; Diabetic Angiopathies - physiopathology; Endothelial cells; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Factor Xa - agonists; Factor Xa - metabolism; Factor Xa Inhibitors - administration & dosage; Humanities and Social Sciences; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Mice; Mice, Knockout; multidisciplinary; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Phosphorylation; Phosphorylation - drug effects; Receptor mechanisms; Receptor, PAR-2 - genetics; Receptor, PAR-2 - metabolism; Rivaroxaban - administration & dosage; Science; Science (multidisciplinary); Streptozocin; Streptozocin - toxicity; Therapeutic applications; Vasodilation; Vasodilation - drug effects; Vasodilation - genetics; Vasodilation - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47474-0

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 eNOS Ser1177 phosphorylation in the aorta ( P  < 0.001). Induction of diabetes to PAR2-deficient (PAR2 −/− ) mice did not affect endothelial function and eNOS Ser1177 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 eNOS Ser1177 phosphorylation ( P  < 0.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings ( P  < 0.001) and eNOS Ser1177 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.