Rivaroxaban, a Specific FXa Inhibitor, Improved Endothelium-dependent Relaxation of Aortic Segments in Diabetic Mice

Overview

Journal Sci Rep

Specialty Science

Date 2019 Aug 3

PMID 31371788

Citations 16

Authors

Phuong Tran Pham

Daiju Fukuda

Shusuke Yagi

Kenya Kusunose

Hirotsugu Yamada

Takeshi Soeki

Michio Shimabukuro

Masataka Sata

Affiliations

Soon will be listed here.

Abstract

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

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