Sergi Torramade-Moix1, Marta Palomo1,2,3, Manel Vera4, Didac Jerez1, Ana Belen Moreno-Castaño1, M Urooj Zafar5, Jordi Rovira6,7, Fritz Diekmann6,7,8, Joan Carles Garcia-Pagan9,10,11, Gines Escolar1, Aleix Cases4, Maribel Diaz-Ricart12,13. 1. Pathology Department, CDB, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain. 2. Hospital Clinic, Josep Carreras Leukaemia Research Institute, University of Barcelona, Barcelona, Spain. 3. Barcelona Endothelium Team (BET), Josep Carreras Leukemia Research Institute, Barcelona, Spain. 4. Nephrology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain. 5. Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA. 6. Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 7. Red de Investigacion Renal (REDINREN), Madrid, Spain. 8. Department of Nephrology and Kidney Transplantation, Institut Clinic de Nefrologia i Urologia (ICNU), Hospital Clinic de Barcelona, Barcelona, Spain. 9. Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 10. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Universidad de Barcelona, Barcelona, Spain. 11. Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), University of Barcelona, Barcelona, Spain. 12. Pathology Department, CDB, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain. mdiaz@clinic.cat. 13. Barcelona Endothelium Team (BET), Josep Carreras Leukemia Research Institute, Barcelona, Spain. mdiaz@clinic.cat.
Abstract
PURPOSE: Chronic kidney disease (CKD) associates with inflammatory and prothrombotic phenotypes, resulting in higher cardiovascular risk. Factor Xa displays functions beyond coagulation, exhibiting proinflammatory effects. The aim of the present study was to investigate whether a direct FXa inhibitor protects from the endothelial dysfunction (ED) caused by uremia. METHODS: Macro (HUVEC) and microvascular (HMEC) endothelial cells (ECs) were exposed to serum from uremic patients or healthy donors, in absence and presence of apixaban (60 ng/ml). We evaluated changes in surface VCAM-1 and ICAM-1, intracellular eNOS, reactive oxygen species (ROS), and von Willebrand Factor (VWF) production by immunofluorescence, reactivity of the extracellular matrix (ECM) towards platelets, and intracellular signaling. RESULTS: ECs exposed to uremic serum triggered dysregulation of all the parameters. Presence of apixaban resulted in decreased expression of VCAM-1 (178 ± 14 to 89 ± 2% on HMEC and 324 ± 71 to 142 ± 25% on HUVEC) and ICAM-1 (388 ± 60 to 111 ± 10% on HMEC and 148 ± 9% to 90 ± 7% on HUVEC); increased eNOS (72 ± 8% to 95 ± 10% on HMEC); normalization of ROS levels (173 ± 21 to 114 ± 13% on HMEC and 165 ± 14 to 127 ± 7% on HUVEC); lower production of VWF (168 ± 14 to 92 ± 4% on HMEC and 151 ± 22 to 99 ± 11% on HUVEC); and decreased platelet adhesion onto ECM (134 ± 22 to 93 ± 23% on HMEC and 161 ± 14 to 117 ± 7% on HUVEC). Apixaban inhibited p38MAPK and p42/44 activation in HUVEC (139 ± 15 to 48 ± 15% and 411 ± 66 to 177 ± 57%, respectively) (p < 0.05 vs control for all parameters). CONCLUSION: Anti-FXa strategies, such as apixaban, prevented ED caused by the uremic milieu, exhibiting anti-inflammatory and antioxidant properties and modulating the reactivity of the ECM.
PURPOSE: Chronic kidney disease (CKD) associates with inflammatory and prothrombotic phenotypes, resulting in higher cardiovascular risk. Factor Xa displays functions beyond coagulation, exhibiting proinflammatory effects. The aim of the present study was to investigate whether a direct FXa inhibitor protects from the endothelial dysfunction (ED) caused by uremia. METHODS: Macro (HUVEC) and microvascular (HMEC) endothelial cells (ECs) were exposed to serum from uremic patients or healthy donors, in absence and presence of apixaban (60 ng/ml). We evaluated changes in surface VCAM-1 and ICAM-1, intracellular eNOS, reactive oxygen species (ROS), and von Willebrand Factor (VWF) production by immunofluorescence, reactivity of the extracellular matrix (ECM) towards platelets, and intracellular signaling. RESULTS: ECs exposed to uremic serum triggered dysregulation of all the parameters. Presence of apixaban resulted in decreased expression of VCAM-1 (178 ± 14 to 89 ± 2% on HMEC and 324 ± 71 to 142 ± 25% on HUVEC) and ICAM-1 (388 ± 60 to 111 ± 10% on HMEC and 148 ± 9% to 90 ± 7% on HUVEC); increased eNOS (72 ± 8% to 95 ± 10% on HMEC); normalization of ROS levels (173 ± 21 to 114 ± 13% on HMEC and 165 ± 14 to 127 ± 7% on HUVEC); lower production of VWF (168 ± 14 to 92 ± 4% on HMEC and 151 ± 22 to 99 ± 11% on HUVEC); and decreased platelet adhesion onto ECM (134 ± 22 to 93 ± 23% on HMEC and 161 ± 14 to 117 ± 7% on HUVEC). Apixaban inhibited p38MAPK and p42/44 activation in HUVEC (139 ± 15 to 48 ± 15% and 411 ± 66 to 177 ± 57%, respectively) (p < 0.05 vs control for all parameters). CONCLUSION: Anti-FXa strategies, such as apixaban, prevented ED caused by the uremic milieu, exhibiting anti-inflammatory and antioxidant properties and modulating the reactivity of the ECM.
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