Full text provided by www.sciencedirect.com Signal transduction induced by activated protein C: no role in protection against sepsis? Sjoukje H. Slofstra 1 , Hugo ten Cate 2 and C. Arnold Spek 1 1 Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands 2 Department of Internal Medicine, Academic Hospital and Cardiovascular Research Institute Maastricht, University of Maastricht, 6200 MD Maastricht, the Netherlands The anticoagulant activated protein C (APC) is histori- cally known as a risk factor for venous thrombosis. However, after the positive results of the protein C worldwide evaluation in severe sepsis (PROWESS) trial, which showed that APC was the first drug that consid- erably reduced sepsis-related mortality, APC is consid- ered a pleiotropic protein with both anticoagulant and anti-inflammatory properties. In addition, in vitro studies have suggested that APC-induced intracellular signal transduction is a potential mechanism by which APC might be protective against sepsis. Recently, however, the efficacy of APC in sepsis has been argued, and also the extent to which the signal transduction capacity of APC contributes to its pro-survival effects is debated. Here, we review the role of APC in the body natural defense against sepsis and discuss the mechanism by which APC might act at a cellular level. The anticoagulant protein C pathway: overview Protein C (PC) is a major physiological anticoagulant. It is a vitamin-K-dependent zymogen of a serine protease (see Glossary), which has an important role in the regulation of blood coagulation (Box 1). After activation by thrombin, activated protein C (APC) proteolytically inactivates coa- gulation factors FVa and FVIIIa, thereby preventing thrombotic complications that are due to excessive fibrin formation. The physiological significance of the PC antic- oagulant activity is evident in individuals with homozy- gous or compound heterozygous PC deficiency. These individuals suffer from massive disseminated intravascu- lar coagulation or neonatal purpura fulminans [1,2]. Indi- viduals with heterozygous PC deficiency, although less affected, are at risk for thrombophlebitis, deep vein throm- bosis or pulmonary embolism [3,4]. Already in the early 1980s, it was shown that adminis- tration of minute amounts of thrombin, which leads to the production of APC, to dogs before infusion of endotoxin improved survival [5]. Direct infusion of APC into baboons challenged with Escherichia coli also improved survival, whereas potent inhibitors of thrombin formation (e.g. active-site-inhibited FXa) in the same model only abolished coagulation abnormalities without affecting the lethal effects of E. coli [6]. These data suggested that APC has direct anti-inflammatory properties. The positive reports from the protein C worldwide evaluation in severe sepsis (PROWESS) trial, which showed that APC considerably reduces sepsis-related mortality [7], further strengthened the appreciation of APC as an anti-inflammatory protein. The potential clinical importance of APC in sepsis directed a large research effort into the underlying mole- cular mechanism by which APC is protective. Several elegant in vitro studies showed that APC can induce intracellular signal transduction, thereby modifying var- ious important physiological processes that are potentially involved in sepsis. Consequently, APC-induced intracellu- lar signaling has been proposed to confer protection in sepsis. However, the exact mechanism by which the APC pathway might control inflammation during sepsis and to what extent the signal transduction capacity of APC contributes to its pro-survival effects remain elusive. The initial enthusiasm about APC as a treatment strat- egy for sepsis faded gradually because it appeared that APC might only be beneficial in a group of selected patients. In addition, only the anticoagulant effect of APC has been proven to be essential in vivo, whereas the relevance of APC-induced signal transduction in vivo is still awaiting confirmation. This review provides an overview of the role of APC in the regulation of blood coagulation, summarizes the role of APC in pathophysiol- ogy with emphasis on sepsis, discusses the intracellular signal transduction pathways induced by APC and criti- cally evaluates both the clinical relevance of APC and the importance of APC-induced signal transduction. Regulation of blood coagulation by APC To prevent thrombotic complications that are due to exces- sive or untimely fibrin formation, blood coagulation is regulated by several anticoagulant pathways. Anticoagu- lants downregulate procoagulant pathways at three differ- ent levels. Tissue factor pathway inhibitor (TFPI) inhibits the activity of the tissue factor (TF)–FVIIa complex; antith- rombin inhibits the proteolytic activities of thrombin and FXa, whereas the APC pathway targets two essential cofactors (FVa and FVIIIa) of the coagulation cascade. After the generation of minute amounts of thrombin, the homologous plasma glycoproteins FV and FVIII are Review TRENDS in Molecular Medicine Vol.12 No.8 Corresponding author: Spek, C.A. (c.a.spek@amc.uva.nl) Available online 3 July 2006 www.sciencedirect.com 1471-4914/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2006.06.003