C‐terminal residues of activated protein C light chain contribute to its anticoagulant and cytoprotective activities

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Activated protein C variants with normal cytoprotective but reduced anticoagulant activity

Recombinant activated protein C (APC), a well-defined anticoagulant enzyme, reduced mortality in severe sepsis patients in a phase 3 trial. However, 2 potent anticoagulants, antithrombin III and recombinant tissue factor pathway inhibitor, failed to do so, implying the physiologic relevance of APC’s less welldefined anti-inflammatory and antiapoptotic activities. Recombinant APC therapy conveys...

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Novel mechanisms for activated protein C cytoprotective activities involving noncanonical activation of protease-activated receptor 3.

The direct cytoprotective activities of activated protein C (APC) on cells convey therapeutic, relevant, beneficial effects in injury and disease models in vivo and require the endothelial protein C receptor (EPCR) and protease activated receptor 1 (PAR1). Thrombin also activates PAR1, but its effects on cells contrast APC's cytoprotective effects. To gain insights into mechanisms for these con...

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Activated protein C variants with normal cytoprotective but reduced anticoagulant activity.

Recombinant activated protein C (APC), a well-defined anticoagulant enzyme, reduced mortality in severe sepsis patients in a phase 3 trial. However, 2 potent anticoagulants, antithrombin III and recombinant tissue factor pathway inhibitor, failed to do so, implying the physiologic relevance of APC's less well-defined anti-inflammatory and antiapoptotic activities. Recombinant APC therapy convey...

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High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C.

Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels are associated, respectively, with either increased risk or apparent protective effects for atherothrombosis. The ability of purified LDL and HDL to downregulate thrombin formation, a contributor to atherothrombotic processes, was assessed. Purified HDL, but not LDL, significantly enhanced inactivation of coagul...

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Role of individual gamma-carboxyglutamic acid residues of activated human protein C in defining its in vitro anticoagulant activity.

To evaluate the contributions of individual gamma-carboxyglutamic acid (gla) residues to the overall Ca(2+)-dependent anticoagulant activity of activated human protein C (APC), we used recombinant (r) DNA technology to generate protein C (PC) variants in which each of the gla precursor glutamic acid (E) residues (positions 6, 7, 14, 16, 19, 20, 25, 26, and 29) was separately altered to aspartic...

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ژورنال

عنوان ژورنال: Journal of Thrombosis and Haemostasis

سال: 2020

ISSN: 1538-7933,1538-7836

DOI: 10.1111/jth.14756