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

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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; endothelial cells; neutrophils; sepsis; thrombomodulin; tumor necrosis factor

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/1570161043476429

Affiliations: Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-0811, Japan.

Publication date: April 1, 2004

More about this publication?
  • Vascular disease is the commonest cause of death in Westernized countries and its incidence is on the increase in developing countries. It follows that considerable research is directed at establishing effective treatment for acute vascular events. Long-term treatment has also received considerable attention (e.g. for symptomatic relief). Furthermore, effective prevention, whether primary or secondary, is backed by the findings of several landmark trials.

    Vascular disease is a complex field with primary care physicians and nurse practitioners as well as several specialties involved. The latter include cardiology, vascular and cardio thoracic surgery, general medicine, radiology, clinical pharmacology and neurology (stroke units). Current Vascular Pharmacology will publish reviews to update all those concerned with the treatment of vascular disease. For example, reviews commenting on recently published trials or new drugs will be included. In addition to clinically relevant topics we will consider 'research-based' reviews dealing with future developments and potential drug targets. Therefore, another function of Current Vascular Pharmacology is to bridge the gap between clinical practice and ongoing research.

    Debates will also be encouraged in the correspondence section of this journal.
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