Gene Expression Profile of Antithrombotic Protein C Defines New Mechanisms Modulating Inflammation and Apoptosis*

By D. Joyce, L. Gelbert, A. Ciaccia, B. Dehoff, B. Grinnell. Journal of Biological Chemistry, 2001

686 citations recorded by the source corpus.

Human protein C is a natural anticoagulant factor, and a recombinant activated form of the molecule (rhAPC) is completing clinical evaluation for treatment of severe sepsis. Because of the pathophysiologic role of endothelial dysfunction in severe inflammatory disease and sepsis, we explored the possibility that rhAPC might directly modulate endothelial function, independent of its anticoagulant activity. Using broad transcriptional profiling, we show that rhAPC directly modulates patterns of endothelial cell gene expression clustering into anti-inflammatory and cell survival pathways. rhAPC directly suppressed expression of p50 and p52 NFκB subunits, resulting in a functional decrease in NFκB binding at target sites. Further, rhAPC blocked expression of downstream NFκB regulated genes following tumor necrosis factor α induction, including dose-dependent suppression of cell adhesion expression and functional binding of intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. Further, rhAPC modulated several genes in the endothelial apoptosis pathway, including the Bcl-2 homologue protein and inhibitor of apoptosis protein. These pathway changes resulted in the ability of rhAPC to inhibit the induction of apoptosis by the potent inducer, staurosporine. This new mechanistic understanding of endothelial regulation and the modulation of tumor necrosis factor-induced endothelial dysfunction creates a novel link between coagulation, inflammation, and cell death and provides insight into the molecular basis for the efficacy of APC in systemic inflammation and sepsis.

Subfields: Epidemiology, Hematology, Immunology

View Paper: https://www.semanticscholar.org/paper/1c81eb3a5456616001bec4c0fdb825f7169a3b2b

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In Epidemiology

Berislav Zlokovic

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Citations in the corpus

The interactions between inflammation and coagulation (2005, background): “The APC–EPCR complex can decrease endothelial cell apoptosis (Joyce et al, 2001), apparently through the activation of PAR 1 (Riewald et al, 2002).”
Pathophysiology of Acute Kidney Injury (2012, positive): “Activated protein C exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling (240).”
Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective (2003, background): “Neither hypoxia nor APC significantly altered the amounts of IAP-1 or the Bcl-2 homolog A1, whereas those two proteins are upregulated by APC in HUVE”