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

Circulation. 2020 Mar 17;141(11):916-930. doi: 10.1161/CIRCULATIONAHA.119.041882. Epub 2020 Jan 29.

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.

Keywords: acid ceramidase; cardioprotective agents; mRNA; myocardial infarction; sphingolipids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Ceramidase / antagonists & inhibitors
  • Acid Ceramidase / genetics
  • Acid Ceramidase / physiology*
  • Animals
  • Animals, Newborn
  • Apoptosis
  • Ceramides / metabolism
  • Cicatrix / pathology
  • Embryoid Bodies
  • Enzyme Induction
  • Female
  • Genetic Therapy*
  • Humans
  • Hypoxia / etiology
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Induced Pluripotent Stem Cells / metabolism
  • Inflammation
  • Male
  • Mice
  • Myocardial Infarction / complications
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Messenger / pharmacology
  • RNA, Messenger / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / metabolism
  • Sphingolipids / metabolism*
  • Transfection
  • Up-Regulation

Substances

  • Ceramides
  • RNA, Messenger
  • Recombinant Proteins
  • Sphingolipids
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • ASAH1 protein, human
  • Acid Ceramidase
  • Asah1 protein, mouse
  • Asah1 protein, rat