Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation

Introduction: Activated protein C (APC) is an important natural anticoagulant that is proteolyticatly generated. from protein C (PC) by the modulation of thrombin activity in the, presence of thrombomodulin on an endothelial surface. Recent studies have demonstrated that, beyond its anticoagulant acitivities, APC had anti-inflammatory and cytoprotective properties The mechanisms underlying APC's anti-inflammatory effects remain unknown. Our goat was to elucidate and confirm these mechanisms. Methods: We first examined the effect of APC on reactive oxygen species (ROS) and inflammatory cytokine production in murine macrophage-like RAW264.7 cells. We further examined the effect of APC on chemically induced lipid peroxidation and advanced glycation end-products (AGE) formation. Results and conclusions: APC in the range of 10-50 mug/mL could reduce lipopolysaccharide (LPS)-induced ROS generation, nuclear factor kappaB (NF-kappaB) activation and resultant proinflammatory cytokine production. Additional cell-free experiments revealed that APC (10-50 mug/mL) had inhibitory effects on lipid peroxidation and AGE formation. These findings suggest that APC, via its intrinsic anti-oxidant properties, may, in settings of oxidant stress, exert important cytoprotective and anti-inflammatory effects that are distinct from its anticoagulant activity as an antioxidant protein. If that is true, APC may contribute to ROS-related chronic disorders including atherosclerosis and diabetes as well as acute shock conditions. (C) 2004 Elsevier Ltd. All rights reserved.