Table_1_Sphingolipid Synthesis Inhibition by Myriocin Administration Enhances Lipid Consumption and Ameliorates Lipid Response to Myocardial Ischemia Reperfusion Injury.xlsx

Myocardial infarct requires prompt thrombolytic therapy or primary percutaneous coronary intervention to limit the extent of necrosis, but reperfusion creates additional damage. Along with reperfusion, a maladaptive remodeling phase might occur and it is often associated with inflammation, oxidative stress, as well as a reduced ability to recover metabolism homeostasis. Infarcted individuals can exhibit reduced lipid turnover and their accumulation in cardiomyocytes, which is linked to a deregulation of peroxisome proliferator activated receptors (PPARs), controlling fatty acids metabolism, energy production, and the anti-inflammatory response. We previously demonstrated that Myriocin can be effectively used as post-conditioning therapeutic to limit ischemia/reperfusion-induced inflammation, oxidative stress, and infarct size, in a murine model. In this follow-up study, we demonstrate that Myriocin has a critical regulatory role in cardiac remodeling and energy production, by up-regulating the transcriptional factor EB, PPARs nuclear receptors and genes involved in fatty acids metabolism, such as VLDL receptor, Fatp1, CD36, Fabp3, Cpts, and mitochondrial FA dehydrogenases. The overall effects are represented by an increased β–oxidation, together with an improved electron transport chain and energy production. The potent immunomodulatory and metabolism regulatory effects of Myriocin elicit the molecule as a promising pharmacological tool for post-conditioning therapy of myocardial ischemia/reperfusion injury.

心肌梗死需及时采取溶栓治疗或直接经皮冠状动脉介入治疗，以限制坏死范围，但再灌注会引发额外的组织损伤。伴随再灌注过程，可能会出现不良心肌重构阶段，该阶段常与炎症、氧化应激以及代谢稳态恢复能力下降相关。心肌梗死患者可出现脂质周转降低以及脂质在心肌细胞内蓄积的情况，这与过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptors, PPARs）失调有关，该受体可调控脂肪酸代谢、能量产生与抗炎反应。我们此前的研究已在小鼠模型中证实，丝菌素（Myriocin）可作为有效的缺血后处理治疗药物，用以减轻缺血/再灌注引发的炎症、氧化应激并缩小梗死面积。在本后续研究中，我们证实丝菌素可通过上调转录因子EB（transcriptional factor EB）、PPARs核受体以及参与脂肪酸代谢的相关基因，如极低密度脂蛋白受体（VLDL receptor）、Fatp1、CD36、Fabp3、Cpts及线粒体脂肪酸脱氢酶，在心脏重构与能量产生过程中发挥关键调控作用。其整体效应表现为β氧化增强，同时电子传递链功能与能量产生能力得到改善。丝菌素具有强大的免疫调节与代谢调控效应，使其有望成为治疗心肌缺血再灌注损伤的缺血后处理疗法候选药理学工具。