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 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.
Highlights
Accumulating evidence suggests that the blood coagulation system participates in various disease processes
The results of our experiments indicated that rivaroxaban ameliorated diabetes-induced endothelial dysfunction and suggested that the inhibition of FXa or PAR2 contributes to this disease context
We found that rivaroxaban, a FXa inhibitor, significantly attenuated endothelial dysfunction in diabetic WT mice, with no alteration of blood glucose level
Summary
Accumulating evidence suggests that the blood coagulation system participates in various disease processes. Activated blood coagulation factor X (FXa) plays a central role in the coagulation cascade, while it elicits various cellular responses in vascular cells through activation of protease activated receptors (PAR)[1,2,3,4,5]. Few studies have examined the role of FXa-PAR2 signaling in the development of endothelial dysfunction in a diabetic condition[28,29,30]. Here, hypothesized that inhibition of FXa by rivaroxaban attenuates the development of endothelial dysfunction in a diabetic condition. To address this hypothesis, we administered rivaroxaban to diabetic wild-type (WT) mice, and examined vascular responses. The results of our experiments indicated that rivaroxaban ameliorated diabetes-induced endothelial dysfunction and suggested that the inhibition of FXa or PAR2 contributes to this disease context
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