A novel fibrinogenase from Agkistrodon acutus venom protects against DIC via direct degradation of thrombosis and activation of protein C.
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.
Department of Pharmacology, Zhongshan Medical College, SUN Yat-Sen University, Guangzhou 510080, China.
Jie-zhen
JZ
Qi
Xi
X
Lin
Jia-shu
JS
Chen
Zhen-hua
ZH
Huang
Bi-tao
BT
Qiu
Peng-xin
PX
Qiu
Guang-mei
GM
Yan
D017836:Agkistrodon / Q000502:physiology*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D003435:Crotalid Venoms / Q000201:enzymology*; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D042783:Endothelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D003435:Crotalid Venoms; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; C051321:SERPINE1 protein, human; C082161:lipopolysaccharide A; D012697:Serine Endopeptidases; C412879:venombin B; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator