Oxidative Stress–Dependent Sphingosine Kinase-1 Inhibition Mediates Monoamine Oxidase A–Associated Cardiac Cell Apoptosis
Open accessAbstract
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.
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Increased concentrations of ceramide may mediate apoptosis in the heart in response to ischemia or drugs or cytokines that promote apoptosis.
“Although there is much evidence that increased concentrations of ceramide may mediate apoptosis in the heart in response to ischemia or drugs or cytokines that promote apoptosis, will promote cytochrome c release and apoptosis when directly applied to cardiomyocytes, and that inhibition of de novo ceramide synthesis prevents palmitate-induced apoptosis in L6 myotubes (75, 82, 276, 355, 368), it”
From Cardiac remodeling in obesity (2008) · cites this paper as [276]
Ceramide promotes cytochrome c release and apoptosis when directly applied to cardiomyocytes.
“Although there is much evidence that increased concentrations of ceramide may mediate apoptosis in the heart in response to ischemia or drugs or cytokines that promote apoptosis, will promote cytochrome c release and apoptosis when directly applied to cardiomyocytes, and that inhibition of de novo ceramide synthesis prevents palmitate-induced apoptosis in L6 myotubes (75, 82, 276, 355, 368), it”
From Cardiac remodeling in obesity (2008) · cites this paper as [276]
Inhibition of de novo ceramide synthesis prevents palmitate-induced apoptosis in L6 myotubes.
“Although there is much evidence that increased concentrations of ceramide may mediate apoptosis in the heart in response to ischemia or drugs or cytokines that promote apoptosis, will promote cytochrome c release and apoptosis when directly applied to cardiomyocytes, and that inhibition of de novo ceramide synthesis prevents palmitate-induced apoptosis in L6 myotubes (75, 82, 276, 355, 368), it”
From Cardiac remodeling in obesity (2008) · cites this paper as [276]
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References 34 · Cited by 195
- Authors
- Pchejetski, D., Kunduzova, O., Dayon, A., Calise, D., Seguelas, M.-H., Leducq, N., Seif, I., Parini, A., & Cuvillier, O.
- Affiliations
- 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,...
- Université Toulouse III - Paul Sabatier (FR)
- Venue
- Circulation Research
- Published
- 2007-01-05
- Volume
- 100
- Issue
- 1
- Pages
- 41-49
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2123227507
- Cited by
- 195
- References
- 34
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 16 · 2020: 18 · 2019: 12 · 2018: 12 · 2017: 13 · 2016: 9 · 2015: 8 · 2014: 13 · 2013: 11 · 2012: 9
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- monoamine oxidase A, sphingosine kinase 1, cardiomyocyte apoptosis, reactive oxygen species, ceramide, sphingosine-1-phosphate, sphingolipid metabolism, oxidative stress, ischemia-reperfusion injury, mitochondrial apoptosis, H9c2 cells, serotonin, hydrogen peroxide
- MeSH terms
- Sphingosine Kinase, Animals, Cells, Cultured, Ceramides, Drug Resistance, Hydrogen Peroxide, Lysophospholipids, Mitochondria, Heart, Monoamine Oxidase, Serotonin, Sphingolipids, Sphingosine, Myocardial Reperfusion Injury, Down-Regulation, Up-Regulation, Oxidants, Rats, Sprague-Dawley, Apoptosis, Reactive Oxygen Species, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Oxidative Stress, Myocytes, Cardiac, Mice, Rats
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