Protective, repairing and fibrinolytic effects of rivaroxaban on vascular endothelium

摘要

Aims Rivaroxaban, a direct inhibitor of activated factor X (FXa), is the only new oral anticoagulant approved for secondary prevention after acute coronary syndrome. Our objective was to identify the possible molecular mechanisms of rivaroxaban that contribute to endothelial function. Methods Cell viability and growth of human umbilical vein endothelial cells (HUVEC) were registered. Gene expression studies comparing the effects of rivaroxaban and FXa were conducted by a selective RNA array and confirmed by protein quantification. Wound‐healing experiments on HUVEC, platelet adhesion, enzymatic activity, and cell‐based assays for fibrin formation were performed with rivaroxaban. Results Rivaroxaban (50?nM) only altered (2 fold change) the expression of matrix metallopeptidase 2 and urokinase plasminogen activator (u‐PA), but counteracted the FXa (9?nM)‐induced upregulation of several pro‐inflammatory genes ( P ??0.05) and FXa‐enhanced platelet adhesion over HUVEC. Rivaroxaban increased u‐PA protein expression in HUVEC supernatants and enhanced u‐PA activity (up to 4?IU?ng ?1 of u‐PA). Rivaroxaban (1?nM–1?μM) showed a significant and dose‐dependent positive effect on HUVEC growth that was inhibited by BC‐11‐hydroxibromide, an inhibitor of u‐PA. Healing properties after a wound on HUVEC cultures, and fibrinolytic properties were also shown by rivaroxaban. Both effects were reversed by BC‐11‐hydroxibromide. Conclusions Rivaroxaban enhanced viability, growth and migration of HUVEC, mainly by u‐PA activation and upregulation, which also participate in the rivaroxaban‐induced fibrinolytic activity at endothelial level. Rivaroxaban also protected from the pro‐inflammatory effects of FXa on HUVEC. Altogether may improve endothelial functionality and could contribute to the cardiovascular benefits of rivaroxaban.