Apixaban Downregulates Endothelial Inflammatory and Prothrombotic Phenotype in an In Vitro Model of Endothelial Dysfunction in Uremia.
Endothelial Cells
/ drug effects
Extracellular Matrix
/ drug effects
Factor Xa Inhibitors
/ pharmacology
Human Umbilical Vein Endothelial Cells
/ drug effects
Humans
Inflammation
/ physiopathology
Intercellular Adhesion Molecule-1
/ drug effects
Nitric Oxide Synthase Type III
/ drug effects
Phenotype
Pyrazoles
/ pharmacology
Pyridones
/ pharmacology
Reactive Oxygen Species
/ metabolism
Signal Transduction
/ drug effects
Uremia
/ physiopathology
Vascular Cell Adhesion Molecule-1
/ drug effects
von Willebrand Factor
/ drug effects
Chronic kidney disease
Direct oral anticoagulant
Endothelial dysfunction
Inflammation
Oxidative stress
Journal
Cardiovascular drugs and therapy
ISSN: 1573-7241
Titre abrégé: Cardiovasc Drugs Ther
Pays: United States
ID NLM: 8712220
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
pubmed:
12
7
2020
medline:
16
12
2021
entrez:
12
7
2020
Statut:
ppublish
Résumé
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. 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. 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). 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.
Identifiants
pubmed: 32651897
doi: 10.1007/s10557-020-07010-z
pii: 10.1007/s10557-020-07010-z
doi:
Substances chimiques
Factor Xa Inhibitors
0
Pyrazoles
0
Pyridones
0
Reactive Oxygen Species
0
Vascular Cell Adhesion Molecule-1
0
von Willebrand Factor
0
Intercellular Adhesion Molecule-1
126547-89-5
apixaban
3Z9Y7UWC1J
Nitric Oxide Synthase Type III
EC 1.14.13.39
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
521-532Références
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