title: Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart.
abstract: Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1(+/-) mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1(+/-) mice 24h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy.
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Klevstig
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lundqvist
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Scharin Täng
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Fogelstrand
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Adiels
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Andersson
authors.affiliation: Memorial Sloan Kettering Cancer Center, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kolesnick
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Jeppsson
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden. Electronic address: malin.levin@wlab.gu.se.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Levin
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D005838:Genotype; D000860:Hypoxia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009026:Mortality; D009154:Mutation; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics*; D018754:Ventricular Dysfunction
chemical_list: D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase
keywords: Acid sphingomyelinase; Bioactive lipids; Ceramide; Myocardial ischemia