Gene expression profile of antithrombotic protein C defines new mechanismsmodulating inflammation and apoptosis

Human protein C is a natural anticoagulant factor, and a recombinant activa ted form of the molecule (rhAPC) is completing clinical evaluation for trea tment of severe sepsis. Because of the pathophysiologic role of endothelial dysfunction in severe inflammatory disease and sepsis, we explored the pos sibility that rhAPC might directly modulate endothelial function, independe nt of its anticoagulant activity. Using broad transcriptional profiling, we show that rhAPC directly modulates patterns of endothelial cell gene expre ssion clustering into anti-inflammatory and cell survival pathways, rhAPC d irectly suppressed expression of p50 and p52 NF kappaB subunits, resulting in a functional decrease in NF kappaB binding at target sites. Further, rhA PC blocked expression of downstream NF kappaB regulated genes following tum or necrosis factor alpha 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, rhA PC modulated several genes in the endothelial apoptosis pathway, including the Bcl-2 homologue protein and inhibitor of apoptosis protein. These pathw ay changes resulted in the ability of rhAPC to inhibit the induction of apo ptosis by the potent inducer, staurosporine. This new mechanistic understan ding of endothelial regulation and the modulation of tumor necrosis factor- induced endothelial dysfunction creates a novel link between coagulation, i nflammation, and cell death and provides insight into the molecular basis f or the efficacy of APC in systemic inflammation and sepsis.