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Int. J. Mol. Sci. 2017, 18(4), 839; doi:10.3390/ijms18040839

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction

1
Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
2
Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
3
Department of Cardiothoracic Surgery, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
4
Institute of Precision Medicine, Furtwangen University, 78054 Villingen-Schwenningen, Germany
5
Department of Anesthesiology and Intensive Care, University of Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany
6
Institute of Pharmacology and Toxicology, Jena University Hospital, Drackendorfer Straße 1, 07747 Jena, Germany
*
Author to whom correspondence should be addressed.
Academic Editors: Tsukasa Nakamura and Eiichi Sato
Received: 11 March 2017 / Revised: 2 April 2017 / Accepted: 10 April 2017 / Published: 15 April 2017
(This article belongs to the Special Issue Sepsis)
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Abstract

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. View Full-Text
Keywords: acid sphingomyelinase; de novo synthesis; ceramide; desipramine; sepsis; cardiac dysfunction acid sphingomyelinase; de novo synthesis; ceramide; desipramine; sepsis; cardiac dysfunction
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MDPI and ACS Style

Chung, H.-Y.; Kollmey, A.S.; Schrepper, A.; Kohl, M.; Bläss, M.F.; Stehr, S.N.; Lupp, A.; Gräler, M.H.; Claus, R.A. Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction. Int. J. Mol. Sci. 2017, 18, 839.

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