Sepsis and the Role of Activated Protein C

2004 ◽  
Vol 24 (6) ◽  
pp. 40-45
Author(s):  
Janice Tazbir
Keyword(s):  
Protein C ◽  
Activated Protein C

Protective role of activated protein C in lung and airway remodeling

2004 ◽  
Vol 32 (Supplement) ◽  
pp. S262-S265 ◽  
Author(s):  
Koji Suzuki ◽  
Esteban Cesar Gabazza ◽  
Tatsuya Hayashi ◽  
Haruhiko Kamada ◽  
Yukihiko Adachi ◽  
...  
Keyword(s):  
Protein C ◽  
Airway Remodeling ◽  
Activated Protein C ◽  
Protective Role

scholarly journals Role of coagulation pathways and treatment with activated protein C in hyperoxic lung injury

Thorax ◽  
2009 ◽  
Vol 64 (2) ◽  
pp. 114-120 ◽  
Author(s):  
M R Looney ◽  
C T Esmon ◽  
M A Matthay
Keyword(s):  
Lung Injury ◽  
Protein C ◽  
Activated Protein C ◽  
Hyperoxic Lung Injury

Role of the A+ Helix in Heparin Binding to Protein C Inhibitor

1996 ◽  
Vol 75 (05) ◽  
pp. 760-766 ◽  
Author(s):  
Marc G L M Elisen ◽  
Machiel H H Maseland ◽  
Frank C Church ◽  
Bonno N Bouma ◽  
Joost C M Meijers
Keyword(s):  
Protein C ◽  
Electrostatic Interactions ◽  
Deletion Mutant ◽  
Activated Protein C ◽  
Structural Features ◽  
Heparin Binding ◽  
Wild Type ◽  
Protein C Inhibitor ◽  
Positively Charged

SummaryInteractions between proteins and heparin(-like) structures involve electrostatic forces and structural features. Based on charge distributions in the linear sequence of protein C inhibitor (PCI), two positively charged regions of PCI were proposed as possible candidates for this interaction. The first region, the A+ helix, is located at the N-terminus (residues 1-11), whereas the second region, the H helix, is positioned between residues 264 and 280 of PCI. Competition experiments with synthetic peptides based on the sequence of these regions demonstrated that the H helix has the highest affinity for heparin. In contrast to previous observations we found that the A+ helix peptide competed for the interaction of PCI with heparin, but its affinity was much lower than that of the H helix peptide.Recombinant PCI was also used to investigate the role of the A+ helix in heparin binding. Full-length (wild-type) rPCI as well as an A+ helix deletion mutant of PCI (rPCI-Δ2-l 1) were expressed in baby hamster kidney cells and both had normal inhibition activity with activated protein C and thrombin. The interaction of the recombinant PCIs with heparin was investigated and compared to plasma PCI. The A+ helix deletion mutant showed a decreased affinity for heparin in inhibition reactions with activated protein C and thrombin, but had similar association constants compared to wild-type rPCI. The synthetic A+ helix peptide competed with rPCI-Δ2-11 for binding to heparin. This indicated that the interaction between PCI and heparin is fairly non-specific and that the interaction is primarily based on electrostatic interactions.In summary, our data suggest that the H helix of PCI is the main heparin binding region of PCI, but the A+ helix increases the overall affinity for the PCI-heparin interaction by contributing a second positively charged region to the surface of PCI.

RNAi-Mediated Inhibition of Activated Protein C- A New Approach for Hemophilia Treatment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1204-1204 ◽  
Author(s):  
Ivanka Toudjarska ◽  
Zuhua Cai ◽  
Tim Racie ◽  
Julia Hettinger ◽  
Stuart Milstein ◽  
...  
Keyword(s):  
Protein C ◽  
Animal Studies ◽  
Limited Proteolysis ◽  
Activated Protein C ◽  
Transgenic Animal ◽  
Injury Model ◽  
Clotting Cascade ◽  
Fv Leiden ◽  
Fvl Mutation

Abstract Abstract 1204 Protein C is a major anticoagulation factor that serves as a key regulator of the clotting cascade. Activated protein C (APC), which is formed by limited proteolysis of the zymogen protein C by the thrombin–thrombomodulin complex, modulates thrombin generation. The anticoagulant effect of APC is due to subsequent inactivation of both activated factors V (FVa) and VIII (FVIIIa). The important role of APC in coagulation is highlighted in FV Leiden (FVL), the most common inherited form of thrombophilia. FVL is caused by a mutation in the FV gene at the initial APC cleavage site, which results in FVL being inactivated at approximately one tenth the rate of normal FVa, leading to high thrombin levels that create a procoagulant state. Several clinical studies have suggested that the severity or onset of bleeding phenotype in hemophilia patients is substantially reduced in association with impaired inactivation of FVa by APC in the presence of the FVL mutation. Transgenic animal studies also show that hemophilic mice, either heterozygous or homozygous for FVL, have improved clotting times with the ability to form clots at sites of laser-induced injury in a microvascular bed injury model, supporting the role of the FVL mutation in enhancing hemostasis. Therapeutic strategies aimed at reducing the level of protein C and activated protein C, thereby increasing levels of FVa and thrombin could thus prove efficacious in hemophilia A and B. Here we investigate the systemic administration of lipid nanoparticle (LNP) formulated siRNA directed against Protein C (encoded by Proc). We have designed potent siRNA sequences against human, cynomologous monkey, dog, mouse and rat Proc mRNA. The lead human/cynomologous candidate has an IC50 of 5pM. The lead mouse/rat candidate has an IC50 of 30 pM and an ED50 of 20 ug/kg. We demonstrate robust and durable inhibition of Proc mRNA in normal mouse liver- a single injection of 0.3 mg/kg resulted in 90% silencing of Proc mRNA and reduction of more than 75% which was sustained for more than two weeks. We also demonstrate significant reduction of circulating protein as measured by Western blot. Further testing using genetic models of hemophilia is being conducted to provide proof-of-concept for developing a Proc siRNA as a novel therapeutic agent in hemophilia management. Disclosures: Toudjarska: Alnylam Pharmaceuticals, Inc.: Employment. Cai:Alnylam Pharmaceuticals, Inc.: Employment. Racie:Alnylam Pharmaceuticals, Inc.: Employment. Hettinger:Alnylam Pharmaceuticals, Inc.: Employment. Milstein:Alnylam Pharmaceuticals, Inc.: Employment. Bettencourt:Alnylam Pharmaceuticals, Inc.: Employment. Sah:Alnylam Pharmaceuticals, Inc.: Employment. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment. Maraganore:Alnylam pharmaceuticals, Inc.: Employment. Vaishnaw:Alnylam Pharmaceuticals, Inc.: Employment.

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