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

• Published in: Cardiovascular drugs and therapy Vol. 26; no. 3; pp. 227 - 237
• Main Authors: Somers, Sarin J., Frias, Miguel, Lacerda, Lydia, Opie, Lionel H., Lecour, Sandrine
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-06-2012; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cardiovascular system; Extracellular Signal-Regulated MAP Kinases - metabolism; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Lysophospholipids - pharmacology; Lysophospholipids - therapeutic use; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Sphingosine - therapeutic use; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; RISK pathway; Ischaemia-reperfusion; SAFE pathway; Sphingosine-1-phosphate; Ischemia reperfusion; Cardioprotective agent; Risk factor
• ISSN: 0920-3206; 1573-7241
• DOI: 10.1007/s10557-012-6376-2

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.