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Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response after Myocardial Infarction


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 (LV) and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze pro-apoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase (Sphk) to produce the pro-survival molecule sphingosine-1-phosphate (S1P). 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 post hypoxia or MI resulted in reduced AC activity and increased cell death; by contrast, enhancing AC activity via AC modRNA treatment increased cell survival post 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 following AC modRNA delivery to decreased ceramide levels, lower cell death rates and changes in the composition of the immune cell population in the LV manifested by lowered abundance of pro-inflammatory 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.

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