Role of sphingosine kinase activity in protection of heart against ischemia reperfusion injury.
BACKGROUND
Sphingosine kinase (SKase) has been implicated in the protection of hearts from ischemia/reperfusion injury. This hypothesis was further examined.


METHODS
Changes in SKase activity and cardiac function (left ventricular developed pressure, LVDP, and infarct size) in response to ischemia and reperfusion were studied in adult rat hearts by the ex vivo Langendorff method. Following initial equilibration or preconditioning, there was 45 min no-flow ischemia and then 45 min of reperfusion.


RESULTS
SKase activity declined 61% during ischemia and did not recover upon reperfusion. LVDP also did not recover upon reperfusion and the infarct size was 47%. A short 30 min period of ischemia was associated with variable recovery of SKase activity that directly correlated with LVDP recovery. Preconditioning of hearts reduced the decrease in SKase activity during ischemia by half, and upon reperfusion activity returned to normal. The LVDP recovered 79% and infarct size was small. Preconditioned hearts had higher S-1-P levels after ischemia/reperfusion relative to non-preconditioned hearts. The decline in SKase activity during ischemia of preconditioned hearts could not be mimicked in vitro by treatment with protein phosphatases. Attempts to alter activity of SKase from control, preconditioned, ischemic, or reperfused hearts by phosphorylation with ERK1/2 were unsuccessful. Treatment of non-preconditioned hearts at reperfusion with 100 nM S-1-P improved recovery of LVDP. The SKase inhibitor dimethylsphingosine blocked hemodynamic recovery in preconditioned hearts.


CONCLUSIONS
The data support a role for SKase activity in recovery of hemodynamic function after ischemic injury and also in the cardioprotective effect of preconditioning.
Vessey
Donald A
DA
Liver Study Unit, Department of Veterans Affairs Medical Center San Francisco CA 94121, USA. donald.vessey@med.va.gov
Kelley
Michael
M
Li
Luyi
L
Huang
Yong
Y
Zhou
Hui-Zhong
HZ
Zhu
Bo Qing
BQ
Karliner
Joel S
JS
D000818:Animals; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D013347:Subcellular Fractions / Q000201:enzymology; D017725:Ventricular Pressure; D000099157:Sphingosine Kinase
D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase