Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation.
BACKGROUND
Activated protein C (APC) is an important natural anticoagulant that is proteolytically 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 goal 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.


CONCLUSIONS
APC in the range of 10-50 microg/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 microg/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.
Yamaji
Kazuyo
K
Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan.
Wang
Yin
Y
Liu
Yan
Y
Abeyama
Kazuhiro
K
Hashiguchi
Teruto
T
Uchimura
Tomonori
T
Krishna Biswas
Kamal
K
Iwamoto
Hisahiko
H
Maruyama
Ikuro
I
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism* / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D002474:Cell-Free System; D003300:Copper / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D017127:Glycation End Products, Advanced / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis; D015227:Lipid Peroxidation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000925:Anticoagulants; D000975:Antioxidants; D016207:Cytokines; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D011486:Protein C; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003300:Copper