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

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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.

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          Most cited references 69

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Tissue sulfhydryl groups

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              A fluorometric method for determination of oxidized and reduced glutathione in tissues.

               R Hilf,  P J Hissin (1976)
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                15 April 2017
                April 2017
                : 18
                : 4
                Affiliations
                [1 ]Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Ha-yeun.Chung@ 123456med.uni-jena.de (H.-Y.C.); sophia.kollmey@ 123456web.de (A.S.K.); Andrea.Schrepper@ 123456med.uni-jena.de (A.S.); sebastian.stehr@ 123456medizin.uni-leipzig.de (S.N.S.); markus.graeler@ 123456med.uni-jena.de (M.H.G.)
                [2 ]Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; blae@ 123456hs-furtwangen.de
                [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; matthias.kohl@ 123456stamats.de
                [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; amelie.lupp@ 123456med.uni-jena.de
                Author notes
                [* ]Correspondence: Ralf.Claus@ 123456med.uni-jena.de ; Tel.: +49-(0)3641-932-5860
                Article
                ijms-18-00839
                10.3390/ijms18040839
                5412423
                28420138
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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