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(Circulation Research. 2007;100:41.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Oxidative Stress–Dependent Sphingosine Kinase-1 Inhibition Mediates Monoamine Oxidase A–Associated Cardiac Cell Apoptosis

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

From Inserm U466 (D.P., A.D., O.C.), Toulouse; Inserm U388 (O.K., M.-H.S., A.P.), Toulouse; IFR 31 (D.C.), Service de Microchirurgie, Toulouse; Université Toulouse III Paul Sabatier (D.P., O.K., A.D., D.C., M.-H.S., A.P., O.C.); Cardiovascular and Thrombosis Department (N.L.), Sanofi-Aventis, Toulouse; and Université Paris-Sud (I.S.), Faculté de Pharmacie, Chatenay-Malabry, France. Current address for D.P., A.D., and O.C.: CNRS, Institut de Pharmacologie et de Biologie Structurale, UMR5089, Toulouse, France.

Correspondence to Dr Olivier Cuvillier, Inserm U466, BP 84225, 31432 Toulouse Cedex 4, France. E-mail olivier.cuvillier{at}ipbs.fr; and Dr Angelo Parini, Inserm U388, BP 84225, 31432 Toulouse Cedex 4, France. E-mail angelo.parini@toulouse.inserm.fr

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 C₂-ceramide or H₂O₂. In contrast, enforced expression of SphK1 protected H9c2 cells from serotonin- or H₂O₂-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.

Key Words: sphingosine kinase-1 • monoamine oxidases • ischemia/reperfusion • ROS • serotonin

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