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

Yoav Hadas, Adam S. Vincek, Elias Youssef, Magdalena M. Żak, Elena Chepurko, Nishat Sultana, Mohammad Tofael Kabir Sharkar, Ningning Guo, Rinat Komargodski, Ann Anu Kurian, Keerat Kaur, Ajit Magadum, Anthony Fargnoli, Michael G. Katz, Nadia Hossain, Ephraim Kenigsberg, Nicole C. Dubois, Eric Schadt, Roger Hajjar, Efrat EliyahuLior Zangi

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)916-930
Number of pages15
JournalCirculation
Volume141
Issue number11
DOIs
StatePublished - 17 Mar 2020

Keywords

  • acid ceramidase
  • cardioprotective agents
  • mRNA
  • myocardial infarction
  • sphingolipids

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