Mosnier, L O; Zampolli, A; Kerschen, E J; Schuepbach, R A; Banerjee, Y; Fernández, J A; Yang, X V; Riewald, M; Weiler, H; Ruggeri, Z M; Griffin, J H (2009). Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant. Blood, 113(23):5970-5978.
Full text not available from this repository.
View at publisher
Activated protein C (APC) reduces mortality in severe sepsis patients. APC exerts anticoagulant activities via inactivation of factors Va and VIIIa and cytoprotective activities via endothelial protein C receptor and protease-activated receptor-1. APC mutants with selectively altered and opposite activity profiles, that is, greatly reduced anticoagulant activity or greatly reduced cytoprotective activities, are compared here. Glu149Ala-APC exhibited enhanced in vitro anticoagulant and in vivo antithrombotic activity, but greatly diminished in vitro cytoprotective effects and in vivo reduction of endotoxin-induced murine mortality. Thus, residue Glu149 and the C-terminal region of APC's light chain are identified as functionally important for expression of multiple APC activities. In contrast to Glu149Ala-APC, 5A-APC (Lys191-193Ala + Arg229/230Ala) with protease domain mutations lacked in vivo antithrombotic activity, although it was potent in reducing endotoxin-induced mortality, as previously shown. These data imply that APC molecular species with potent antithrombotic activity, but without robust cytoprotective activity, are not sufficient to reduce mortality in endotoxemia, emphasizing the need for APC's cytoprotective actions, but not anticoagulant actions, to reduce endotoxin-induced mortality. Protein engineering can provide APC mutants that permit definitive mechanism of action studies for APC's multiple activities, and may also provide safer and more effective second-generation APC mutants with reduced bleeding risk.
0 downloads since deposited on 12 Feb 2010
0 downloads since 12 months
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Intensive Care Medicine
|DDC:||610 Medicine & health|
|Deposited On:||12 Feb 2010 17:49|
|Last Modified:||27 Nov 2013 16:33|
|Publisher:||American Society of Hematology|
Users (please log in): suggest update or correction for this item
Repository Staff Only: item control page