Ezequiel Álvarez1,2, Beatriz Paradela-Dobarro1,2, Sergio Raposeiras-Roubín1,3, José Ramón González-Juanatey1,2,3. 1. Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana s/n, Santiago de Compostela, 15706, A Coruña, Spain. 2. CIBERCV, Madrid, Spain. 3. Servicio de Cardiología y Unidad de Hemodinámica, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana s/n, Santiago de Compostela, 15706, A Coruña, Spain.
Abstract
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.
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.
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