Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction
| Autor: | Ralf A. Claus, Matthias Kohl, Andrea Schrepper, Ha-Yeun Chung, Amelie Lupp, Markus Bläss, Markus H. Gräler, Sebastian Stehr, Anna S Kollmey |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cardiomyopathy 030204 cardiovascular system & hematology sepsis Mice chemistry.chemical_compound 0302 clinical medicine Desipramine acid sphingomyelinase Cardiac Output Spectroscopy Mice Knockout cardiac dysfunction General Medicine Computer Science Applications Sphingomyelin Phosphodiesterase Female Acid sphingomyelinase medicine.drug Cardiac function curve medicine.medical_specialty Ceramide de novo synthesis ceramide desipramine Heart Diseases Mice Transgenic Biology Ceramides Article Catalysis Inorganic Chemistry Sepsis 03 medical and health sciences Internal medicine medicine Animals Physical and Theoretical Chemistry Molecular Biology L-Lactate Dehydrogenase Gene Expression Profiling Myocardium Troponin I Organic Chemistry Lipid signaling Lipid Metabolism medicine.disease Disease Models Animal Oxidative Stress 030104 developmental biology Endocrinology Gene Expression Regulation chemistry Heart failure Biomarkers |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 18; Issue 4; Pages: 839 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms18040839 |
| Popis: | Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients’ mortality. Acid sphingomyelinase (SMPD1)—the principal regulator for rapid and transient generation of the lipid mediator ceramide—is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1+/+ as well as SMPD1−/− animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1−/− littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|