title: Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C.
abstract: In sepsis, the severity-dependent decrease of von Willebrand factor (VWF)-inactivating protease, a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), results in platelet aggregation and consumption, leading to sepsis-associated thrombotic microangiopathy (TMA) and organ failure. Previous reports assessing its functional deficiency have pinpointed involvement of autoantibodies or mutations to propagate thrombotic thrombocytopenic purpura (TTP). However, mechanisms of acquired ADAMTS13 deficiency during host response remain unclear. To enhance understanding of ADAMTS13 deficiency in sepsis, we evaluated changes in expression of mRNA coding ADAMTS13 during septic conditions using primary cellular sources of the protease. We hypothesized that proinflammatory cytokines and constituents of serum from septic patients affect the transcriptional level of ADAMTS13 in vitro, and previously recommended therapeutic agents as adjunctive therapy for sepsis interact therewith. Cultured hepatic stellate cells (HSCs), endothelial cells (HMEC) and human precision-cut liver slices as an ex vivo model were stimulated with sepsis prototypic cytokines, bacterial endotoxin and pooled serum obtained from septic patients. Stimulation resulted in a significant decrease in ADAMTS13 mRNA between 10% and 80% of basal transcriptional rates. Costimulation of selenite or recombinant activated protein C (APC) with serum prevented ADAMTS13 decrease in HSCs and increased ADAMTS13 transcripts in HMEC. In archived clinical samples, the activity of ADAMTS13 in septic patients treated with APC (n = 5) increased with an accompanying decrease in VWF propeptide as surrogate for improved endothelial function. In conclusion, proinflammatory conditions of sepsis repress mRNA coding ADAMTS13 and the ameliorating effect by selenite and APC may support the concept for identification of beneficial mechanisms triggered by these drugs at a molecular level.
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Michael L
authors: ML
authors: Ekaney
authors: Department of Nephropathology, University Hospital Aachen, Aachen, Germany.
authors: Clemens L
authors: CL
authors: Bockmeyer
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Maik
authors: M
authors: Sossdorf
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Philipp A
authors: PA
authors: Reuken
authors: Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Florian
authors: F
authors: Conradi
authors: Department for Interdisciplinary Intensive Care, University Hospital Aachen, Aachen, Germany.
authors: Tobias
authors: T
authors: Schuerholz
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Markus F
authors: MF
authors: Blaess
authors: Mount Sinai School of Medicine, New York, New York, United States of America.
authors: Scott L
authors: SL
authors: Friedman
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Wolfgang
authors: W
authors: Lösche
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Michael
authors: M
authors: Bauer
authors: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors: Ralf A
authors: RA
authors: Claus
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism*; D000071120:ADAMTS13 Protein; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D011486:Protein C / Q000378:metabolism*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics*; D020887:Selenious Acid / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D011486:Protein C; D012333:RNA, Messenger; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D020887:Selenious Acid