Jurnal Internasional Sphingomyelinase asam memainkan peran penting dalam aktivitas prokoagulan faktor jaringan yang diinduksi LPS dan sitokin

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Jurnal Internasional Sphingomyelinase asam memainkan peran penting dalam aktivitas prokoagulan faktor jaringan yang diinduksi LPS dan sitokin

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Abstract Abstract

Abstract

Abstract Tissue factor (TF) is a cofactor for factor VIIa and the main cellular initiator of coagulation. Usually, most of the TF on the cell surface is in a cryptic-inactive coagulant state but is transformed into a procoagulant (decryption) form after cell activation. Our recent study in cell model systems shows that sphingomyelin (SM) in the outer leaflets of the plasma membrane is responsible for maintaining TF in an encrypted state in resting cells, and the hydrolysis of SM causes the TF decryption. This study was conducted to investigate the relevance of this new mechanism in the regulation of TF procoagulant activity in pathophysiology. As observed in the cell system, administration of adenosine triphosphate (ATP) to mice increases the activity of TF-induced procoagulants in monocytes. Treatment of mice with pharmacological inhibitors of acid sphingomyelinase (ASMase), desipramine and imipramine, weakening of ATP-induced TF decryption. Interestingly, ASMase inhibitors also block LPS-induced TF procoagulant activity without affecting LPS-induced TF protein synthesis. Additional studies show that LPS induces ASMase translocation to leaflets outside the plasma membrane and reduces levels of BC in monocytes. Research using macrophages and endothelial cells derived from human monocytes further confirms the role of ASMase in the cytokine-induced TF procoagulant activity. Overall, our data suggest that TF procoagulant activity induced by LPS or cytokines requires decryption of the newly synthesized TF protein by SM hydrolysis as mediated by ASMase. The observation that ASMase inhibitors weaken TF-induced coagulation increases the possibility of their therapeutic use in treating thrombotic disorders associated with deviant expression of TF.

  • Submitted May 1, 2019.
  • Received June 24, 2019. [19659010] © 2019 by The American Society of Hematology

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