Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischaemia-reperfusion.
OBJECTIVE
Several experimental studies have demonstrated protection against cardiac ischaemia-reperfusion injury achieved by pre-treatment with exogenous sphingosine-1-phosphate (S1P). We tested the hypothesis that pharmacological S1P receptor agonists improve recovery of function when applied with reperfusion.


RESULTS
Isolated rat cardiomyocytes were stimulated with exogenous S1P, the selective S1P1 receptor agonist SEW2871, or the S1P1/3 receptor agonist FTY720. Western blot analysis was performed to analyse downstream signalling pathways. Ischaemia-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. 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 ischaemia-reperfusion. In isolated rat hearts, treatment with FTY720 during reperfusion attenuated the rise in left ventricular end-diastolic pressure (LVEDP) and improved the 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 ischaemia-reperfusion model also demonstrated improved functional recovery induced by FTY720 treatment during reperfusion.


CONCLUSIONS
Pharmacological S1P receptor agonists have distinct effects on ischaemia-reperfusion injury. Their efficacy when applied during reperfusion makes them potential candidates for pharmaceutical postconditioning therapy after cardiac ischaemia.
Department of Internal Medicine I, University of Würzburg, Medizinische Klinik und Poliklinik I, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. hofmann_u2@klinik.uni-wuerzburg.de
Ulrich
U
Hofmann
Natalie
N
Burkard
Carolin
C
Vogt
Annemarie
A
Thoma
Stefan
S
Frantz
Georg
G
Ertl
Oliver
O
Ritter
Andreas
A
Bonz
D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010069:Oxadiazoles / Q000494:pharmacology*; D010477:Perfusion; D011409:Propylene Glycols / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D002316:Cardiotonic Agents; D008246:Lysophospholipids; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C060506:sphingosine 1-phosphate; C483803:Egfr protein, rat; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine