Copyright © 2007, European Society of Cardiology
A sphingosine kinase 1 mutation sensitizes the myocardium to ischemia/reperfusion injury
aCardiology Section, VA Medical Center and University of California, San Francisco, CA 94121, U.S.A.
bLiver Study Unit, Veterans Affairs Medical Center and Department of Medicine, University of California, San Francisco, CA 94121, U.S.A.
cDrug Studies Unit, Department of Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, CA 94143, U.S.A.
dCardiovascular Research Institute, University of California, San Francisco, CA 94143, U.S.A.
*Corresponding author. Cardiology Section (111C5), 4150 Clement Street, San Francisco, CA 94121, U.S.A. Tel.: +1 415 221 4810x3171; fax: +1 415 750 6959. joel.karliner{at}med.va.gov
Objective Sphingosine kinase (SphK) is a key enzyme in the synthesis of sphingosine 1-phosphate (S1P), a bioactive sphingolipid. SphK is involved in ischemic preconditioning (IPC). To date no studies in genetically altered animals have examined the role of SphK1 in myocardial ischemia/reperfusion (IR) injury and IPC.
Methods and results Wild-type and SphK1 null mouse hearts were subjected to IR (50 min global ischemia and 40 min reperfusion) in a Langendorff apparatus. IPC consisted of 2 min of global ischemia and 2 min of reperfusion for two cycles. At baseline, there were no differences in left ventricular developed pressure (LVDP), ±dP/dtmax, and LV end-diastolic pressure (EDP) between SphK1 mutant and wild-type (WT) mouse hearts. In the mutants, total SphK enzyme activity was reduced by 44% and S1P levels were decreased by 41%. SphK1 null hearts subjected to IR exhibited more cardiac damage compared with WT: LVDP and ±dP/dtmax decreased, LVEDP increased, and infarct size increased (n=6, P<0.05). Apoptosis was markedly enhanced in SphK1 mutant IR mouse hearts. IPC was cardioprotective in WT hearts, but this protection appeared to be ineffective in SphK1 null hearts. There was no change in infarct size in the IPC+IR group compared to the IR group in the null hearts (50.1±5.0% vs 45.0±3.8%, n=6, P=NS). IPC remained ineffective in the null hearts even when the index ischemia time was shortened by 10 min.
Conclusions Deletion of the SphK1 gene sensitizes the myocardium to IR injury and appears to impair the protective effect of IPC. These data provide the first genetic evidence that the SphK1-S1P pathway is a critical mediator of IPC and cell survival.
KEYWORDS Ischemia; Myocardial infarction; Sphingosine kinase; Sphingosine 1-phosphate; Cardioprotection; Signal transduction
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