Prevention of Endothelial Cell Injury by Activated Protein C: The Molecular Mechanism(s) and Therapeutic Implications

Kenji      Okajima

doi:10.2174/1570161043476429

Abstract

Activated protein C (APC), a natural anticoagulant, is formed from protein C by the action of thrombin bound to thrombomodulin on the endothelial cell surface. APC regulates the coagulation system by inactivating the activated form of factors V and VIII in the presence of protein S. Tumor necrosis factor-α(TNF-α) plays critical roles in the development of disseminated intravascular coagulation, acute respiratory distress syndrome and shock in sepsis by inducing endothelial cell damage through activation of neutrophils. APC reduces the pulmonary endothelial cell injury and hypotension in rats administered endotoxin (ET) by inhibiting TNF-α production through inhibition of its transcription. Furthermore, APC reduces the ischemia / reperfusion-induced renal injury and the stress-induced gastric mucosal injury in rats. Inhibition by APC of the endothelial cell damage inhibited the decrease in the endothelial production of prostacyclin in vivo . These therapeutic effects could not be attributed to its anticoagulant effects, but to inhibition of TNF-α production. APC inhibits ET-induced TNF-α production in vitro in human monocytes by inhibiting activation of NFkB and AP-1 by inhibiting degradation of IkB and mitogen-activated protein kinase pathways, respectively. Recombinant APC was reported to reduce the mortality of patients with severe sepsis. These observations strongly suggest that APC might be involved not only in regulation of the coagulation system, but in regulation of inflammatory responses by preventing endothelial cell injury. Furthermore, APC reduced the spinal cord injury induced by compression-trauma or ischemia / reperfusion by inhibiting TNF-α production in rats, suggesting that APC may be a potential therapeutic agent for spinal cord injury in which only limited therapeutic measures are currently available.

Keywords: activated protein c, thrombomodulin, endothelial cells, tumor necrosis factor, sepsis, neutrophils

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