title: S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart.
abstract: Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes cardiomyocyte survival and contributes to ischemic preconditioning. S1P lyase (SPL) is a stress-activated enzyme responsible for irreversible S1P catabolism. We hypothesized that SPL contributes to oxidative stress by depleting S1P pools available for cardioprotective signaling. Accordingly, we evaluated SPL inhibition as a strategy for reducing cardiac ischemia-reperfusion (I/R) injury. We measured SPL expression and enzyme activity in murine hearts. Basal SPL activity was low in wild-type cardiac tissue but was activated in response to 50 min of ischemia (n = 5, P < 0.01). Hearts of heterozygous SPL knockout mice exhibited reduced SPL activity, elevated S1P levels, smaller infarct size, and increased functional recovery after I/R compared with littermate controls (n = 5, P < 0.01). The small molecule tetrahydroxybutylimidazole (THI) is a Federal Drug Administration-approved food additive that inhibits SPL. When given overnight at 25 mg/l in drinking water, THI raised S1P levels and reduced SPL activity (n = 5, P < 0.01). THI reduced infarct size and enhanced hemodynamic recovery in response to 50 min of ischemia and to 40 min of reperfusion in ex vivo hearts (n = 7, P < .01). These data correlated with an increase in MAP kinase-interacting serine/threonine kinase 1, eukaryotic translation initiation factor 4E, and ribosomal protein S6 phosphorylation levels after I/R, suggesting that SPL inhibition enhances protein translation. Pretreatment with an S1P₁ and S1P₃ receptor antagonist partially reversed the effects of THI. These results reveal, for the first time, that SPL is an ischemia-induced enzyme that can be targeted as a novel strategy for preventing cardiac I/R injury.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609-1673, USA.
authors.forename: Padmavathi
authors.initials: P
authors.lastname: Bandhuvula
authors.forename: Norman
authors.initials: N
authors.lastname: Honbo
authors.forename: Guan-Ying
authors.initials: GY
authors.lastname: Wang
authors.forename: Zhu-Qiu
authors.initials: ZQ
authors.lastname: Jin
authors.forename: Henrik
authors.initials: H
authors.lastname: Fyrst
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.forename: Lisa
authors.initials: L
authors.lastname: Dillard
authors.forename: Joel S
authors.initials: JS
authors.lastname: Karliner
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine