Document Detail

A sphingosine kinase 1 mutation sensitizes the myocardium to ischemia/reperfusion injury.
MedLine Citation:
PMID:  17610857     Owner:  NLM     Status:  MEDLINE    
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.
Zhu-Qiu Jin; Jianqing Zhang; Yong Huang; Holly E Hoover; Donald A Vessey; Joel S Karliner
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-06-08
Journal Detail:
Title:  Cardiovascular research     Volume:  76     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-09-10     Completed Date:  2008-03-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  41-50     Citation Subset:  IM    
Cardiology Section, VA Medical Center and University of California, San Francisco, CA 94121, USA.
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MeSH Terms
Blotting, Western / methods
Creatine Kinase / analysis,  metabolism
Disease Susceptibility
In Situ Nick-End Labeling
Ischemic Preconditioning, Myocardial
Lysophospholipids / metabolism
Mice, Knockout
Myocardium / enzymology*,  pathology
Phosphotransferases (Alcohol Group Acceptor) / analysis,  genetics,  metabolism*
Reperfusion Injury / enzymology*,  pathology
Sphingosine / analogs & derivatives,  metabolism
Grant Support
1P01 HL068738-01A1/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Lysophospholipids; 123-78-4/Sphingosine; 26993-30-6/sphingosine 1-phosphate; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase; EC Kinase
Comment In:
Cardiovasc Res. 2007 Oct 1;76(1):3-4   [PMID:  17706621 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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