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Acid sphingomyelinase plays a critical role in LPS- and cytokine-induced tissue factor procoagulant activity

Jue Wang, Usha R. Pendurthi and L. Vijaya Mohan Rao

Key Points

  • LPS-induced TF procoagulant activity in monocytes in vivo is dependent on LPS-induced activation of acid sphingomyelinase (ASMase).

  • ASMase inhibitors attenuate LPS- and cytokine-induced TF procoagulant activity without decreasing the de novo synthesis of TF protein.

Abstract

Tissue factor (TF) is a cofactor for factor VIIa and the primary cellular initiator of the coagulation. Typically, most of TF on cell surfaces exist in a cryptic, coagulant inactive state, but transformed to a procoagulant form (decryption) following cell activation. Our recent studies in cell model systems showed that sphingomyelin (SM) in the outer leaflet of the plasma membrane is responsible for maintaining TF in an encrypted state in resting cells and the hydrolysis of SM leads to decryption of TF. The present study was carried out to investigate the relevance of this novel mechanism in the regulation of TF procoagulant activity in pathophysiology. As observed in cell systems, administration of ATP to mice enhanced LPS-induced TF procoagulant activity in monocytes. Treatment of mice with pharmacological inhibitors of ASMase, desipramine and imipramine, attenuated ATP-induced TF decryption. Interestingly, ASMase inhibitors also blocked LPS-induced TF procoagulant activity without affecting the LPS-induced de novo synthesis of TF protein. Additional studies showed that LPS induced translocation of ASMase to the outer leaflet of the plasma membrane and reduced SM levels in monocytes. Studies using human monocyte-derived macrophages and endothelial cells further confirmed the role of ASMase in LPS- and cytokine-induced TF procoagulant activity. Overall, our data indicate that LPS- or cytokine-induced TF procoagulant activity requires the de-encryption of newly synthesized TF protein by ASMase-mediated hydrolysis of SM. The observation that ASMase inhibitors attenuate TF-induced coagulation raises the possibility of their therapeutic use in treating thrombotic disorders associated with aberrant expression of TF.

  • Submitted May 1, 2019.
  • Revision received June 28, 2019.
  • Accepted June 24, 2019.