29 Stimulation of PCI activity in vivo could therefore not only increase the risk for thrombotic events, but also result in the suppression of anti-inflammatory and antiapoptotic activities. 25–27 Besides its role in coagulation, aPC decreases inflammatory responses, partially by inhibition of nuclear translocation of nuclear factor-kappa B, 26–28 and blocks vascular and neuronal toxicities of tissue plasminogen activator. The protein C system represents a major anticoagulant pathway, and genetic defects affecting the protein C system are the most common risk factors for thrombotic diseases. It has been shown by Nishioka et al 24 that the phospholipid phosphatidylethanolamine (PE) can bind to PCI and stimulate its inhibitory activity toward aPC, suggesting that phospholipids are important endogenous cofactors of PCI. PCI and annexin V were found to be endogenously colocalized in atherosclerotic plaques, supporting the hypothesis that exposure of oxidized PE and/or PS may be important for the local regulation of PCI activity in vivo. A heparin-like effect of phospholipids (OxPE) was not seen with antithrombin III, another heparin-binding serpin, suggesting that it is specific for PCI.

No stimulatory effect of phospholipids on aPC inhibition was seen with a PCI mutant lacking the heparin-binding site. A peptide corresponding to the heparin-binding site of PCI abolished the stimulatory effect of PS on aPC inhibition.

PS and OxPE stimulated the inhibition of activated protein C (aPC) by PCI in a Ca ++-dependent manner, indicating that binding of both, aPC (Ca ++ dependent) and PCI (Ca ++ independent), to phospholipids is necessary. Binding to OxPE and PS was competed by heparin, but not by the aminophospholipid-binding protein annexin V or the PCI-binding lipid retinoic acid. PCI bound to oxidized PE (OxPE), and oxidized and unoxidized phosphatidylserine (PS) immobilized on microtiter plates and in aqueous suspension. We analyzed the interaction of PCI with different phospholipids and their oxidized forms. Protein C inhibitor (PCI) is a serpin with affinity for heparin and phosphatidylethanolamine (PE).

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