Chung Ha-Yeun, Kollmey Anna S, Schrepper Andrea, Kohl Matthias, Bläss Markus F, Stehr Sebastian N, Lupp Amelie, Gräler Markus H, Claus Ralf A
Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
Int J Mol Sci. 2017 Apr 15;18(4):839. doi: 10.3390/ijms18040839.
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.
心脏功能障碍，尤其是左心室功能障碍，是脓毒症中常见的早期事件，并且与患者死亡率增加密切相关。酸性鞘磷脂酶（SMPD1）——脂质介质神经酰胺快速短暂生成的主要调节因子——参与脓毒症宿主反应的调节以及慢性心力衰竭的发病机制。本研究使用基因缺陷动物和经药物治疗的动物，在多微生物脓毒症模型中确定了SMPD1及其调节对脓毒症诱导的心肌病的影响程度和潜在作用。作为脓毒症诱导心肌病的替代参数，发现地昔帕明治疗的动物心脏功能、氧化应激标志物以及肌钙蛋白I水平有所改善，地昔帕明是神经酰胺形成的抑制剂。此外，SMPD1缺陷和野生型动物心脏组织中的神经酰胺形成均失调，而地昔帕明预处理导致宿主反应期间神经酰胺含量稳定但增加。这是从头合成增加的结果。引人注目的是，地昔帕明治疗导致替代标志物水平显著改善。此外，地昔帕明预处理的SMPD1同窝仔的类似结果表明存在一条不依赖SMPD1的途径。最后，对细胞凋亡以及抗氧化和细胞因子反应调节重要的差异表达转录本模式支持了地昔帕明调节神经酰胺形成从而产生有益心肌作用的概念。我们描述了地昔帕明在脓毒症诱导的心脏功能障碍期间控制神经酰胺含量的一种新的保护作用。此外，通过用美国食品药品监督管理局（FDA）批准的药物地昔帕明进行预处理，有可能在宿主反应期间调节心脏功能。
