Sphingosine-1-phosphate (S1P) is a bioactive mediator in inflammation. Dysregulated S1P is demonstrated as a cause of heart failure (HF). However, the time-dependent and integrative role of S1P interaction with receptors in HF is unclear after myocardial infarction (MI). In this study, the sphingolipid mediators were quantified in ischemic human hearts. We also measured the time-kinetics of these mediators post-MI in murine spleen and heart as an integrative approach to understand the interaction of S1P and respective S1P receptors in the transition of acute (AHF) to chronic HF (CHF). Risk-free 8-12 weeks male C57BL/6 mice were subjected to MI surgery, and MI was confirmed by echocardiography and histology. Mass spectrometry was used to quantify sphingolipids in plasma, infarcted heart, spleen of mice, and ischemic and healthy human heart. The physiological cardiac repair was observed in mice with a notable increase of S1P quantity (pmol/g) in the heart and spleen significantly reduced in patients with ischemic HF. The circulating murine S1P levels were increased during AHF and CHF despite lowered substrate in CHF. The S1PR1 receptor expression was observed to coincide with the respective S1P quantity in mice and human hearts. Furthermore, selective S1P1 agonist limited inflammatory markers CCL2 and TNF-α and accelerated reparative markers ARG-1 and YM-1 in macrophages in the presence of Kdo2-Lipid A (KLA; potent inflammatory stimulant). This report demonstrated the importance of S1P/S1PR1 signaling in physiological inflammation during cardiac repair in mice. Alteration in these axes may serve as the signs of pathological remodeling in ischemic patients.

中文翻译：

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脾脏和心脏中的 1-磷酸鞘氨醇相互作用反映了小鼠心脏修复程度和人类心脏衰竭

1-磷酸鞘氨醇 (S1P) 是炎症的生物活性介质。失调的 S1P 被证明是心力衰竭 (HF) 的一个原因。然而，在心肌梗塞 (MI) 后，S1P 与 HF 受体相互作用的时间依赖性和综合作用尚不清楚。在这项研究中，对缺血性人类心脏中的鞘脂介质进行了量化。我们还测量了小鼠脾脏和心脏 MI 后这些介质的时间动力学，作为了解 S1P 和相应 S1P 受体在急性 (AHF) 向慢性 HF (CHF) 转变过程中相互作用的综合方法。无风险 8-12 周雄性 C57BL/6 小鼠接受 MI 手术，并通过超声心动图和组织学确认 MI。质谱法用于量化血浆、梗塞心脏、小鼠脾脏以及缺血和健康人心脏中的鞘脂。在小鼠中观察到生理性心脏修复，缺血性 HF 患者心脏和脾脏中 S1P 量 (pmol/g) 显着增加显着降低。尽管 CHF 中的底物降低，但在 AHF 和 CHF 期间循环鼠 S1P 水平增加。观察到 S1PR1 受体表达与小鼠和人类心脏中各自的 S1P 数量一致。此外，在存在 Kdo2-Lipid A（KLA；强效炎症刺激剂）的情况下，选择性 S1P1 激动剂限制了巨噬细胞中的炎症标志物 CCL2 和 TNF-α，并加速了修复标志物 ARG-1 和 YM-1。该报告证明了 S1P/S1PR1 信号在小鼠心脏修复过程中的生理炎症中的重要性。这些轴的改变可能是缺血患者病理重塑的迹象。