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Cardiovasc Res. 2016 Mar 1;109(3):385-96. doi: 10.1093/cvr/cvw004. Epub 2016 Jan 13.

Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43.

Author information

1
Department of Pathology and Immunology, University of Geneva, CMU, F06.2747.a, Rue Michel-Servet 1, Geneva 1211, Switzerland sandrine.morel@unige.ch.
2
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen 2100, Denmark Department of Biomedical Sciences, Copenhagen 2200, Denmark.
3
Department of Biomedical Sciences, Copenhagen 2200, Denmark The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen 2200, Denmark.
4
Department of Medical Specialties-Cardiology, University of Geneva, Geneva 1211, Switzerland.
5
Department of Pathology and Immunology, University of Geneva, CMU, F06.2747.a, Rue Michel-Servet 1, Geneva 1211, Switzerland.
6
Department of Medical Specialties-Endocrinology, Diabetology, Hypertension and Nutrition, University of Geneva, Geneva 1211, Switzerland.
7
Department of Cellular and Physiological Science, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
8
Department of Pediatrics, University of Geneva, Geneva 1211, Switzerland Department of Cell Physiology and Metabolism, University of Geneva, Geneva 1211, Switzerland.
9
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
10
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen 2100, Denmark Department of Biomedical Sciences, Copenhagen 2200, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen 2100, Denmark.
11
Department of Pathology and Immunology, University of Geneva, CMU, F06.2747.a, Rue Michel-Servet 1, Geneva 1211, Switzerland Department of Medical Specialties-Cardiology, University of Geneva, Geneva 1211, Switzerland.

Abstract

AIM:

Increasing evidence points to lipoprotein composition rather than reverse cholesterol transport in the cardioprotective properties of high-density lipoproteins (HDLs). HDL binding to receptors at the surface of cardiomyocytes activates signalling pathways promoting survival, but downstream targets are largely unknown. Here, we investigate the pathways by which the sphingosine-1-phosphate (S1P) constituent of HDL limits cell death induced by cardiac ischaemia-reperfusion (I/R).

METHODS AND RESULTS:

Apolipoprotein M (ApoM) transgenic (Apom-Tg) mice, in which plasma S1P is increased by 296%, and wild-type (WT) mice were subjected to in vivo I/R. Infarct size, neutrophil infiltration into the infarcted area, and serum Troponin I were less pronounced in Apom-Tg mice. In vitro experiments suggest that this cardioprotection depends on direct effects of S1P on cardiomyocytes, whereas leucocyte recruitment seems only indirectly affected. Importantly, short-term S1P treatment at the onset of reperfusion was sufficient to reduce I/R injury in isolated perfused hearts. Mechanistic in vitro and ex vivo studies revealed that 5 min of S1P treatment induced phosphorylation of the gap junction protein Connexin43 (Cx43) on Serine368 (S368), which was mediated by S1P2 and S1P3, but not by S1P1, receptors in cardiomyocytes. Finally, S1P-induced reduction of infarct size after ex vivo I/R was lost in hearts of mice with a truncated C-terminus of Cx43 (Cx43(K258/KO)) or in which the S368 is mutated to a non-phosphorylatable alanine (Cx43(S368A/S368A)).

CONCLUSION:

Our study reveals an important molecular pathway by which modulating the apoM/S1P axis has a therapeutic potential in the fight against I/R injury in the heart.

KEYWORDS:

Connexin43; Ischaemia–reperfusion injury; Sphingosine-1-phosphate

PMID:
26762268
PMCID:
PMC4752044
[Available on 2017-03-01]
DOI:
10.1093/cvr/cvw004
[Indexed for MEDLINE]
Free PMC Article

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