Role of the lectin-like domain of thrombomodulin in septic cardiomyopathy
Maria Theresa Voelker1, Nadine Hechaichi2, Bernadin Ndongson-Dongmo3
1Department of Anaesthesiology and Critical Care Medicine, University Hospital Leipzig, Germany.
Insights
The lectin-like domain of thrombomodulin (LLD-TM) is crucial for maintaining cardiac function during sepsis. Its absence exacerbates septic cardiomyopathy, increasing disease severity and reducing survival.
Area of Science:
- Cardiovascular Biology
- Sepsis Pathophysiology
- Molecular Medicine
Background:
- Septic cardiomyopathy is a serious complication of sepsis and septic shock.
- Thrombomodulin (TM) and its lectin-like domain (LLD-TM) play a role in sepsis, but their specific contribution to cardiac dysfunction is not fully understood.
- Understanding the molecular mechanisms linking LLD-TM, inflammatory mediators, and cardiac function is critical for developing targeted therapies.
Purpose of the Study:
- To investigate the role of thrombomodulin's lectin-like domain (LLD-TM) in the development of septic cardiomyopathy.
- To explore the relationship between LLD-TM, High Mobility Group Box-1 (HMGB-1), and Toll-Like Receptors 2/4 (TLR 2/4) in the context of sepsis-induced cardiac dysfunction.
- To elucidate the intracellular mechanisms underlying reduced cardiac function during sepsis.
Main Methods:
- Sepsis was induced in wildtype and LLD-TM deficient mice (TM^LeD/LeD) using a polymicrobial peritoneal infection model.
- Cardiac function and disease severity were assessed in vivo.
- Cardiomyocyte cultures from wildtype and TM^LeD/LeD mice were used for in vitro studies, including transfection with thrombomodulin variants and blockade of TLR-2/TLR-4.
Main Results:
- Absence of LLD-TM significantly increased disease severity, decreased survival, and impaired cardiac function in septic mice.
- In vitro studies revealed high levels of inflammatory cytokines causing cardio-depression, with a strong correlation between elevated HMGB-1 and troponin-1 levels.
- No association was found between HMGB-1 and TLR-2/TLR-4 signaling, nor between LLD-TM and phospholamban-mediated calcium dysregulation.
Conclusions:
- The lectin-like domain of thrombomodulin (LLD-TM) is essential for maintaining cardiac function and survival during sepsis.
- Toll-Like Receptors 2 and 4 (TLR-2 and TLR-4) are not involved in mediating the development of septic cardiomyopathy.
- LLD-TM deficiency exacerbates sepsis severity and impairs cardiac function, highlighting its protective role.
Aims:
Septic cardiomyopathy is a severe complication of sepsis and septic shock. This study aimed to evaluate the role of thrombomodulin and its lectin-like domain (LLD-TM) in the development of septic cardiomyopathy and the link between LLD-TM, HMGB-1, and toll-like receptors 2/4 (TLR 2/4) to intracellular mechanisms resulting in reduced cardiac function.
Materials And Methods:
Sepsis was induced using a polymicrobial peritoneal infection model in wildtype and mice lacking the lectin-like domain of thrombomodulin (TMLeD/LeD), and severity of disease and cardiac function was compared. Cell cultures of cardiomyocytes were prepared from hearts harvested from wildtype and TMLeD/LeD mice. Cultures of neonatal cardiomyocytes were transfected with complete human thrombomodulin or human thrombomodulin deficient of LLD-TM and when TLR-2 and/or TLR-4 were blocked. All cultures were challenged with inflammatory stimuli.
Key Findings:
Lack of the LLD-TM results in a significant increase in severity of disease, decreased survival and impaired cardiac function in septic mice. In vivo and in vitro analyses of cardiomyocytes displayed high levels of inflammatory cytokines causing cardio-depression. In vitro results showed a strong correlation between elevated HMGB-1 levels and elevated troponin-1 levels. No connection was found between HMGB-1 and TLR-2 and/or -4 signalling pathways. Phospholamban mediated dysregulation of calcium homeostasis resulted in a general impairment after sepsis induction, but showed no connection to LLD-TM.
Significance:
Lack of LLD-TM results in an increase in general severity of disease, decreased survival and impaired cardiac function in sepsis. TLR-2 and TLR 4 do not participate as mediating factors in the development of septic cardiomyopathy.
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