A novel fibrinogenase from Agkistrodon acutus venom protects against DIC via direct degradation of thrombosis and activation of protein C

• Published in: Biochemical pharmacology Vol. 84; no. 7; pp. 905 - 913
• Main Authors: Qi, Jie-zhen, Lin, Xi, Chen, Jia-shu, Huang, Zhen-hua, Qiu, Peng-xin, Yan, Guang-mei
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.10.2012
• Subjects: activated protein C; Agkistrodon; Agkistrodon - physiology; Agkistrodon acutus; Animal models; Animals; antithrombin; blood platelet count; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - pathology; Chemical and Drug Induced Liver Injury - prevention & control; Clinical trials; coagulation; Crotalid Venoms - enzymology; Cytokines; DIC; Disseminated intravascular coagulation; Disseminated Intravascular Coagulation - chemically induced; Disseminated Intravascular Coagulation - drug therapy; Disseminated Intravascular Coagulation - prevention & control; Endothelial Cells - drug effects; Fibrinogen; Fibrinogenase; Fibrinolysis; Gene Expression Regulation - drug effects; Human Umbilical Vein Endothelial Cells; Humans; in vitro studies; Kidney; Kidney Diseases - chemically induced; Kidney Diseases - drug therapy; Kidney Diseases - prevention & control; Lipopolysaccharide; Lipopolysaccharides - toxicity; Liver; Male; Microthrombi; Mortality; pharmacology; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Platelets; Protein C; Protein C - genetics; Protein C - metabolism; Proteinase; Rabbits; Serine Endopeptidases - metabolism; Serine Endopeptidases - pharmacology; Serine Endopeptidases - therapeutic use; Supplementation; survival rate; thrombin; Thrombosis; Thrombosis - drug therapy; Thrombosis - metabolism; Tissue factor; Tissue Plasminogen Activator - drug effects; Tissue Plasminogen Activator - genetics; Tissue Plasminogen Activator - metabolism; Urokinase-Type Plasminogen Activator - drug effects; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; Venom; venoms; PT; EGF; VEGF; Fibrinogenase; Protein C; LPS; AT-III; APTT; FDP; APC; TNF-α; Lipopolysaccharide; PAI-1; FIIa; Microthrombi; u-PA; HUVECs; DIC; t-PA
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2012.06.011

The incidence of disseminated intravascular coagulation (DIC), which leads to multiple organ dysfunction and high mortality, has remained constant in recent years. At present, treatments of DIC have focused on preventing cytokine induction, inhibiting coagulation processes and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC. To better understand the mechanism of treatment on DIC, we here report a novel fibrinogenase from Agkistrodon acutus (FIIa) that effectively protected against LPS-induced DIC in a rabbit model, and detected the tissue factors expression in HUVE cells after using FIIa. In vivo, administration of FIIa reduced hepatic and renal damage, increased the concentration of fibrinogen, the activities of protein C, the platelet count, APTT, PT, FDP, the level of AT-III and t-PA, decreased the level of PAI-1, and increased survival rate in LPS-induced DIC rabbits. In vitro experiments, we further confirmed that FIIa up-regulated the expression of t-PA and u-PA, down-regulated the expression of PAI-1, and directly activated protein C. Our findings suggest that FIIa could effectively protect against DIC via direct degradation of microthrombi and activation of protein C as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease.