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

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.