Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis

Dmitry Pchejetski, Oxana Kunduzova, Audrey Dayon, Denis Calise, Marie-Hélène Seguelas, Nathalie Leducq, Isabelle Seif, Angelo Parini, Olivier Cuvillier

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The mitochondrial enzyme monoamine oxidase (MAO), its isoform MAO-A, plays a major role in reactive oxygen species-dependent cardiomyocyte apoptosis and postischemic cardiac damage. In the current study, we investigated whether sphingolipid metabolism can account for mediating MAO-A- and reactive oxygen species-dependent cardiomyocyte apoptosis. In H9c2 cardiomyoblasts, MAO-A-dependent reactive oxygen species generation led to mitochondria-mediated apoptosis, along with sphingosine kinase-1 (SphK1) inhibition. These phenomena were associated with generation of proapoptotic ceramide and decrease in prosurvival sphingosine 1-phosphate. These events were mimicked by inhibition of SphK1 with either pharmacological inhibitor or small interfering RNA, as well as by extracellular addition of C(2)-ceramide or H(2)O(2). In contrast, enforced expression of SphK1 protected H9c2 cells from serotonin- or H(2)O(2)-induced apoptosis. Analysis of cardiac tissues from wild-type mice subjected to ischemia/reperfusion revealed significant upregulation of ceramide and inhibition of SphK1. It is noteworthy that SphK1 inhibition, ceramide accumulation, and concomitantly infarct size and cardiomyocyte apoptosis were significantly decreased in MAO-A-deficient animals. In conclusion, we show for the first time that the upregulation of ceramide/sphingosine 1-phosphate ratio is a critical event in MAO-A-mediated cardiac cell apoptosis. In addition, we provide the first evidence linking generation of reactive oxygen species with SphK1 inhibition. Finally, we propose sphingolipid metabolites as key mediators of postischemic/reperfusion cardiac injury.
Original languageEnglish
Pages (from-to)41-9
Number of pages9
JournalCirculation Research
Issue number1
Publication statusPublished - 5 Jan 2007


  • Animals
  • Apoptosis
  • Cells, Cultured
  • Ceramides
  • Down-Regulation
  • Drug Resistance
  • Hydrogen Peroxide
  • Lysophospholipids
  • Mice
  • Mice, Knockout
  • Mitochondria, Heart
  • Monoamine Oxidase
  • Myocardial Reperfusion Injury
  • Myocytes, Cardiac
  • Oxidants
  • Oxidative Stress
  • Phosphotransferases (Alcohol Group Acceptor)
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species
  • Serotonin
  • Sphingolipids
  • Sphingosine
  • Up-Regulation

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