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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 5, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp137
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischemia-reperfusion

Ulrich Hofmann*, Natalie Burkard, Carolin Vogt, Annemarie Thoma, Stefan Frantz, Georg Ertl, Oliver Ritter and Andreas Bonz

University of Würzburg, Department of Internal Medicine I

* Corresponding author: Ulrich DW Hofmann, University of Würzburg, Medizinische Klinik und Poliklinik I, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany, Phone: +49 931 201 1, Fax: +49 931 201 36280, hofmann_u2{at}klinik.uni-wuerzburg.de

Aims: Several experimental studies have demonstrated protection against cardiac ischemia-reperfusion injury achieved by pretreatment with exogenous sphingosine-1-phosphate (S1P). We tested the hypothesis that pharmacological S1P receptor agonists improve recovery of function when applied with reperfusion.

Methods: Isolated rat cardiomyocytes were stimulated with exogenous sphingosine-1-phosphate (S1P), the selective S1P1 receptor agonist SEW2871, or the S1P1/3 receptor agonist FTY720. Western blot analysis was performed to analyse downstream signalling pathways. Ischemia-reperfusion studies were conducted in rat cardiomyocytes, isolated Langendorff-perfused rat hearts and in human myocardial muscle strip preparations to evaluate the effect of S1P receptor agonists on cell death and recovery of mechanical function.

Results: All S1P receptor agonists were able to activate Akt. This was associated with transactivation of the epidermal growth factor receptor. In isolated cardiomyocytes, selective stimulation of the S1P1 receptor by SEW2871 induced protection against cell death when administered either before or after ischemia-reperfusion. In isolated rat hearts, treatment with FTY720 during reperfusion attenuated the rise in end-diastolic pressure (LVEDP) and improved recovery of left ventricular developed pressure without limiting infarct size. However, selective S1P1 receptor stimulation did not improve functional recovery but rather increased LVEDP. Additional experiments employing a human myocardial ischemia-reperfusion model also demonstrated improved functional recovery induced by FTY720 treatment during reperfusion.

Conclusion: Pharmacological S1P receptor agonists have distinct effects on ischemia-reperfusion injury. Their efficacy when applied during reperfusion makes them potential candidates for pharmaceutical postconditioning therapy after cardiac ischemia.

KEYWORDS sphingosine-1-phosphate; FTY720; myocardial ischemia-reperfusion injury

Time for primary review: 24 Days


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