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

Kazuyo Yamaji, Yin Wang, Yan Liu, Kazuhiro Abeyama, Teruto Hashiguchi, Tomonori Uchimura, Kamal Krishna Biswas, Hisahiko Iwamoto, Ikuro Maruyama

Research output: Contribution to journalArticle

Abstract

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. 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. APC in the range of 10-50 μg/mL could reduce lipopolysaccharide (LPS)-induced ROS generation, nuclear factor κB (NF-κB) activation and resultant proinflammatory cytokine production. Additional cell-free experiments revealed that APC (10-50 μg/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.

Original languageEnglish (US)
Pages (from-to)319-325
Number of pages7
JournalThrombosis research
Volume115
Issue number4
DOIs
StatePublished - 2005

Keywords

  • Activated protein C
  • Advanced glycation end products
  • Lipid peroxidation
  • Reactive oxygen species

ASJC Scopus subject areas

  • Hematology

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    Yamaji, K., Wang, Y., Liu, Y., Abeyama, K., Hashiguchi, T., Uchimura, T., Krishna Biswas, K., Iwamoto, H., & Maruyama, I. (2005). Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation. Thrombosis research, 115(4), 319-325. https://doi.org/10.1016/j.thromres.2004.09.011