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Sphingosine-1-phosphate (S1P) activates STAT3 to protect against de novo acute heart failure (AHF)

Gaurang P Deshpande1, Aqeela Imamdin1, Sandrine Lecour1

  • 1Hatter Institute for cardiovascular Research in Africa, Department of Medicine, University of Cape Town, South Africa.

Life Sciences
|January 27, 2018
PubMed

Insights

Sphingosine-1-phosphate (S1P) protects hearts in acute heart failure (AHF) by activating signal transducer and activator of transcription 3 (STAT3). This finding supports S1P as a potential therapy for AHF patients.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Pharmacology

Background:

  • Acute heart failure (AHF) presents a significant clinical challenge due to high mortality and re-hospitalization rates.
  • Previous research indicated that sphingosine-1-phosphate (S1P) offers cardioprotection in an ex-vivo AHF model, but the underlying mechanisms required further investigation.

Purpose of the Study:

  • To investigate the role of the signal transducer and activator of transcription 3 (STAT3) pathway in mediating the cardioprotective effects of S1P in acute heart failure.
  • To elucidate the molecular mechanisms by which S1P improves functional recovery in an ex-vivo model of AHF.

Main Methods:

  • Isolated rat hearts underwent a 35-minute hypotensive acute heart failure (AHF) insult followed by a 30-minute recovery period.
  • Sphingosine-1-phosphate (S1P) was administered during either the hypotensive or recovery phase, with or without the STAT3 inhibitor AG490.
  • Functional parameters, including heart rate and left ventricular developed pressure, were continuously monitored.

Main Results:

  • S1P administration during the recovery phase significantly improved heart rate (175.2 ± 30.7 BPM vs. 71.6 ± 27.4 BPM, p < 0.05) compared to controls, without altering left ventricular developed pressure.
  • This cardioprotective effect was correlated with increased levels of phosphorylated STAT3 in the heart's nucleus.
  • Inhibition of STAT3 with AG490 abolished the beneficial effects of S1P on heart rate (42.3 ± 17.1 BPM vs. 148.8 ± 26.4 BPM for S1P, p < 0.05).

Conclusions:

  • The findings demonstrate that S1P confers cardioprotection in an ex-vivo rat heart model of AHF through the activation of the STAT3 signaling pathway.
  • These results provide compelling evidence supporting the potential therapeutic utility of S1P for managing patients with acute heart failure.
Abstract

Keywords:
Acute heart failureCardioprotectionSTAT3Sphingosine-1-phosphate

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