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Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated
Michael L Ekaney1,2, Clemens L Bockmeyer3, Maik Sossdorf1,2
1Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
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.
Insights
Sepsis decreases ADAMTS13 protease mRNA, causing organ damage. Selenite and activated protein C (APC) show potential to counteract this sepsis-induced deficiency and improve endothelial function.
Area of Science:
- Biochemistry
- Molecular Biology
- Pathophysiology
Background:
- Sepsis-associated thrombotic microangiopathy (TMA) is linked to decreased activity of von Willebrand factor (VWF)-inactivating protease, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13).
- Mechanisms underlying acquired ADAMTS13 deficiency during sepsis remain unclear, hindering effective therapeutic strategies.
- Previous research implicated autoantibodies or mutations in thrombotic thrombocytopenic purpura (TTP), but acquired deficiency in sepsis requires further investigation.
Purpose of the Study:
- To investigate the impact of sepsis-related factors on the transcriptional regulation of ADAMTS13.
- To explore the potential of therapeutic agents, selenite and recombinant activated protein C (APC), in modulating ADAMTS13 expression during sepsis.
- To elucidate the molecular mechanisms behind ADAMTS13 deficiency in sepsis and its potential therapeutic interventions.
Main Methods:
- Primary cellular sources, including hepatic stellate cells (HSCs) and human microvascular endothelial cells (HMECs), were utilized.
- An ex vivo model using human precision-cut liver slices was employed to mimic sepsis conditions.
- Cells and tissues were stimulated with pro-inflammatory cytokines, bacterial endotoxin, and serum from septic patients, with or without selenite or APC.
Main Results:
- Stimulation with sepsis-related factors significantly decreased ADAMTS13 mRNA levels in cultured cells and liver slices.
- Co-administration of selenite or APC with serum prevented the decrease in ADAMTS13 mRNA in HSCs and enhanced it in HMECs.
- Clinical data showed increased ADAMTS13 activity and improved endothelial function (decreased VWF propeptide) in septic patients treated with APC.
Conclusions:
- Pro-inflammatory conditions in sepsis suppress the transcription of ADAMTS13.
- Selenite and APC demonstrate a protective effect against sepsis-induced ADAMTS13 downregulation.
- These findings suggest potential therapeutic benefits of selenite and APC by targeting molecular mechanisms of ADAMTS13 regulation in sepsis.
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