Abstract
Fibroblast growth factor-21 (FGF-21) performs a wide range of biological functions in organisms. Here, we report for the first time that FGF-21 suppresses thrombus formation with no notable risk of bleeding. Prophylactic and therapeutic administration of FGF-21 significantly improved the degree of vascular stenosis and reduced the thrombus area, volume and burden. We determined the antithrombotic mechanism of FGF-21, demonstrating that FGF-21 exhibits an anticoagulant effect by inhibiting the expression and activity of factor VII (FVII). FGF-21 exerts an antiplatelet effect by inhibiting platelet activation. FGF-21 enhances fibrinolysis by promoting tissue plasminogen activator (tPA) expression and activation, while inhibiting plasminogen activator inhibitor 1 (PAI-1) expression and activation. We further found that FGF-21 mediated the expression and activation of tPA and PAI-1 by regulating the ERK1/2 and TGF-β/Smad2 pathways, respectively. In addition, we found that FGF-21 inhibits the expression of inflammatory factors in thrombosis by regulating the NF-κB pathway.
© 2022. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Coagulation / drug effects*
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Cell Line
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Cytokines / metabolism
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Disease Models, Animal
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Factor VII / genetics
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Factor VII / metabolism
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Fibrinolysis / drug effects
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Fibrinolytic Agents / pharmacology*
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism
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Fibroblast Growth Factors / pharmacology*
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Humans
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Male
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Mice
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Mice, Inbred ICR
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NF-kappa B / metabolism
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Plasminogen Activator Inhibitor 1 / genetics
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Plasminogen Activator Inhibitor 1 / metabolism
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Platelet Activation / drug effects
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Rabbits
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Signal Transduction
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Smad2 Protein / metabolism
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Thrombosis / blood
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Thrombosis / genetics
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Thrombosis / prevention & control*
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Tissue Plasminogen Activator / genetics
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Tissue Plasminogen Activator / metabolism
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Transforming Growth Factor beta / metabolism
Substances
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Cytokines
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Fibrinolytic Agents
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NF-kappa B
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Plasminogen Activator Inhibitor 1
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Smad2 Protein
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Smad2 protein, mouse
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Transforming Growth Factor beta
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fibroblast growth factor 21
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Fibroblast Growth Factors
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Factor VII
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Extracellular Signal-Regulated MAP Kinases
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Tissue Plasminogen Activator