Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction
Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction
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DOI：
10.1161/circulationaha.119.041882
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发表时间：
2020-03-17
期刊：
影响因子：
37.8
通讯作者：
Zangi, Lior
中科院分区：
文献类型：
--
作者：
Hadas, Yoav;Vincek, Adam S.;Zangi, Lior
背景：鞘脂最近成为心肌梗死（MI）后复发和死亡的生物标志物。正如几个研究小组所证实的，急性MI期间哺乳动物心脏组织中神经酰胺水平的增加与左心室中较高的细胞死亡率和心脏功能恶化有关。神经酰胺酶是唯一已知的水解促凋亡神经酰胺的酶，它产生鞘氨醇，然后鞘氨醇被鞘氨醇激酶磷酸化，产生促存活分子鞘氨醇-1-磷酸。我们假设，酸性神经酰胺酶（AC）过表达将抵消升高的神经酰胺的负面影响，促进细胞存活，从而提供心肌梗死后的心脏保护。方法：我们进行了转录组，鞘脂和蛋白质分析，以评估鞘脂代谢和信号传导后MI。我们研究了改变神经酰胺代谢的影响，通过损失（化学抑制剂）或增益（修改后的mRNA [modRNA]）AC功能后缺氧或MI。结果：我们发现，参与从头神经酰胺合成的几个基因上调，神经酰胺（C16，C20，C20：1，和C24）水平有显着增加MI后24小时。缺氧或MI后AC抑制导致AC活性降低和细胞死亡增加。相比之下，通过AC modRNA处理增强AC活性增加了缺氧或MI后的细胞存活。MI后28天，AC modRNA治疗的小鼠具有比对照小鼠显著更好的心脏功能、更长的存活时间和更小的瘢痕大小。我们归因于AC modRNA交付后MI的心脏功能的改善，以降低神经酰胺水平，降低细胞死亡率，并在左心室的免疫细胞群的组成的变化表现为降低丰度的促炎性有害neutrophils.Conclusions：我们的研究结果表明，通过AC过表达短暂改变鞘脂代谢是足够的和必要的，以诱导心肌保护后MI，从而突出AC modRNA在缺血性心脏病的治疗潜力。
Background:Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI.Methods:We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI.Results:We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils.Conclusions:Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.