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Molecular Medicine

, Volume 21, Issue 1, pp 355–363 | Cite as

Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C

  • Michael L. Ekaney
  • Clemens L. Bockmeyer
  • Maik Sossdorf
  • Philipp A. Reuken
  • Florian Conradi
  • Tobias Schuerholz
  • Markus F. Blaess
  • Scott L. Friedman
  • Wolfgang Lösche
  • Michael Bauer
  • Ralf A. Claus
Research Article

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.

Notes

Acknowledgments

The authors thank Gordon Philipp Otto, Sina Coldewey, Brigitte Specht, Barbara Schmidt and Edith Walther for their technical support and helpful comments. The authors acknowledge Utz Settmacher for providing surgical waste material and Dieter Muller for assistance in handling HPLS. This study was supported by grants from the German Research Foundation to RA Claus (DFG CL 173/4–1); German Federal Ministry of Education and Research within the Center for Sepsis Control and Care (grant 01 EO 1002, Project D1.9; PhD fellowship to ML Ekaney); and by the United States National Institutes of Health (DK56621 to SL Friedman).

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© The Author(s) 2015

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Authors and Affiliations

  • Michael L. Ekaney
    • 1
    • 2
  • Clemens L. Bockmeyer
    • 3
  • Maik Sossdorf
    • 1
    • 2
  • Philipp A. Reuken
    • 1
    • 2
  • Florian Conradi
    • 2
  • Tobias Schuerholz
    • 4
  • Markus F. Blaess
    • 1
    • 2
  • Scott L. Friedman
    • 5
  • Wolfgang Lösche
    • 1
    • 2
  • Michael Bauer
    • 1
    • 2
  • Ralf A. Claus
    • 1
    • 2
  1. 1.Center for Sepsis Control and Care, and Clinic for Anaesthesiology and Intensive Care TherapyJena University HospitalJenaGermany
  2. 2.Clinic for Anaesthesiology and Intensive Care MedicineJena University HospitalJenaGermany
  3. 3.Department of NephropathologyUniversity Hospital AachenAachenGermany
  4. 4.Department for Interdisciplinary Intensive CareUniversity Hospital AachenAachenGermany
  5. 5.Mount Sinai School of MedicineNew YorkUSA

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