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Interplay Between SAFE and RISK Pathways in Sphingosine-1-Phosphate–Induced Cardioprotection

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Abstract

Purpose

We studied the role of two powerful molecular signalling mechanisms involved in the cardioprotective effect of sphingosine-1-phosphate (S1P), a major component of high density lipoprotein (HDL) against myocardial ischaemic-reperfusion injury, namely the RISK pathway (Akt/Erk), including its downstream target FOXO-1 and, the SAFE pathway (TNF/STAT-3).

Methods

Control hearts from wildtype, TNF deficient (TNF−/−) or cardiomyocyte STAT-3 deficient (STAT-3−/−) male mice were perfused on a Langendorff apparatus (35 min global ischaemia and 45 min reperfusion). S1P (10 nM) was given at the onset of reperfusion for the first 7 min, with/without STAT-3 or Akt inhibitors, AG490 and wortmannin (W), respectively.

Results

S1P reduced myocardial infarct size in wildtype hearts (39.3 ± 4.4% in control vs 17.3 ± 3.1% in S1P-treated hearts; n ≥ 6; p < 0.05) but not in STAT-3−/− or TNF−/− mice (34.2 ± 4.3% in STAT-3−/− and 34.1 ± 2.0% in TNF−/− mice; n ≥ 6; p = ns vs. their respective control). Both STAT-3 and Akt inhibitors abolished the protective effects of S1P (33.7 ± 3.3% in S1P + AG490 and 36.6 ± 4.9% in S1P + W; n = 6; p = ns vs. their respective control). Increased nuclear levels of phosphorylated STAT-3 (pSTAT-3), Akt and FOXO-1 were observed at 15 min reperfusion in wildtype mice with Western Blot analysis (53% STAT-3, 47% Akt, 41% FOXO-1; p < 0.05 vs control) but not in STAT-3−/− mice or in wiltype hearts treated with the Akt inhibitor. Interestingly, an activation of pSTAT-3 was noticed in the mitochondria at 7 min but not 15 min of reperfusion.

Conclusions

In conclusion, S1P activates both the SAFE and RISK pathways, therefore suggesting a dual protective signalling in S1P-induced cardioprotection.

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Acknowledgements

Part of this work was supported by the University of Cape Town, the National Research Foundation, the South African Medical Research Council and the Swiss-South African Research grant (PRJ #). Sarin J Somers was supported by Jan Minners Scholarship and Miguel Frias was supported by the Fonds National Suisse.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Hatter Cardiovascular Research Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Sarin J. Somers, Miguel Frias, Lydia Lacerda, Lionel H. Opie & Sandrine Lecour

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  1. Sarin J. Somers
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  2. Miguel Frias
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  3. Lydia Lacerda
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  4. Lionel H. Opie
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Correspondence to Sarin J. Somers.

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Somers, S.J., Frias, M., Lacerda, L. et al. Interplay Between SAFE and RISK Pathways in Sphingosine-1-Phosphate–Induced Cardioprotection. Cardiovasc Drugs Ther 26, 227–237 (2012). https://doi.org/10.1007/s10557-012-6376-2

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