title: Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis.
abstract: 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.
authors.affiliation: Inserm U466, Toulouse Cedex 4, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Pchejetski
authors.forename: Oxana
authors.initials: O
authors.lastname: Kunduzova
authors.forename: Audrey
authors.initials: A
authors.lastname: Dayon
authors.forename: Denis
authors.initials: D
authors.lastname: Calise
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Seguelas
authors.forename: Nathalie
authors.initials: N
authors.lastname: Leducq
authors.forename: Isabelle
authors.initials: I
authors.lastname: Seif
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.forename: Olivier
authors.initials: O
authors.lastname: Cuvillier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation; D004351:Drug Resistance / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology; D008995:Monoamine Oxidase / Q000172:deficiency / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D000099157:Sphingosine Kinase
chemical_list: D002518:Ceramides; D006861:Hydrogen Peroxide; D008246:Lysophospholipids; D008995:Monoamine Oxidase; D016877:Oxidants; D017853:Phosphotransferases (Alcohol Group Acceptor); D017382:Reactive Oxygen Species; D012701:Serotonin; D013107:Sphingolipids; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate