Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 11, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn065
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Ischemic Postconditioning Protects Isolated Mouse Hearts against Ischemia/Reperfusion Injury via Sphingosine Kinase Isoform 1 Activation
Liver Study Unit and Department of Medicine, University of California, San Francisco, CA 94121
* Cardiology Section, Veterans Affairs Medical Center and Department of Medicine, University of California, San Francisco, CA 94121
# Cardiovascular Research Institute, University of California, San Francisco, CA 94143
Correspondence to Donald A. Vessey, Ph.D., Liver Study Unit (151-K), 4150 Clement Street, San Francisco, CA 94121, U.S.A. Tel: 415-750-2088, Fax: 415-750-6906 e-mail: donald.vessey{at}va.gov
Aim: Sphingosine-1-phosphate (S1P) plays a vital role in cytoskeletal rearrangement, development, and apoptosis. Sphingosine kinase 1 (SphK1), the key enzyme catalyzing the formation of S1P, mediates ischemic preconditioning. Ischemic postconditioning (POST) has been shown to protect hearts against ischemia/reperfusion injury (IR). To date no studies have examined the role of SphK1 in POST.
Methods and Results: Wild-type (WT) and SphK1 null (KO) mouse hearts were subjected to IR (45 min of global ischemia and 45 min of reperfusion) in a Langendorff apparatus. Left ventricular developed pressure (LVDP), maximum velocity of increase or decrease of LV pressure (+/- dP/dtmax), and LV end-diastolic pressure (LVEDP) were recorded. Infarction size was measured by 1% triphenyltetrazolium chloride staining. POST, consisting of 5 seconds of ischemia and 5 seconds of reperfusion for 3 cycles after the index ischemia, protected hearts against IR: recovery of LVDP and +/- dP/dtmax were elevated; LVEDP was decreased; infarction size (% of risk area) was reduced from 40±2% in the control group to 29±2 % of the risk area in the POST group (P<0.05, n=4/group). Phosphorylation of Akt and ERK (extracellular signal-regulated kinases) detected by Western blotting was increased at 10 min of reperfusion. The protection induced by POST was abolished in KO hearts. Infarction size in KO hearts (57±5 %) was not different from the KO control group (53±5 % of risk area, n=4, P=N.S.).
Conclusions: A short period of reperfusion/ischemia protected wild-type mouse hearts against IR. The cardiac protection induced by POST was abrogated in SphK1-KO mouse hearts. Thus, SphK1 is critical for successful ischemic postconditioning.
KEYWORDS ischemia; preconditioning; postconditioning; sphingosine kinase; signal transduction
Time for primary review: 30 days
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