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

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Morel, S, Christoffersen, C, Axelsen, LN, Montecucco, F, Rochemont, V, Frias, MA, Mach, F, James, RW, Naus, CC, Chanson, M, Lampe, PD, Nielsen, MS, Nielsen, LB & Kwak, BR 2016, 'Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43' Cardiovascular Research, bind 109, nr. 3, s. 385-96. https://doi.org/10.1093/cvr/cvw004

APA

CBE

Morel S, Christoffersen C, Axelsen LN, Montecucco F, Rochemont V, Frias MA, Mach F, James RW, Naus CC, Chanson M, Lampe PD, Nielsen MS, Nielsen LB, Kwak BR. 2016. Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43. Cardiovascular Research. 109(3):385-96. https://doi.org/10.1093/cvr/cvw004

MLA

Vancouver

Author

Morel, Sandrine ; Christoffersen, Christina ; Axelsen, Lene N ; Montecucco, Fabrizio ; Rochemont, Viviane ; Frias, Miguel A ; Mach, Francois ; James, Richard W ; Naus, Christian C ; Chanson, Marc ; Lampe, Paul D ; Nielsen, Morten S ; Nielsen, Lars B ; Kwak, Brenda R. / Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43. I: Cardiovascular Research. 2016 ; Bind 109, Nr. 3. s. 385-96.

Bibtex

@article{deb4d27a67ff4da794aa760d80a0baeb,
title = "Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43",
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 = "Journal Article, Research Support, Non-U.S. Gov't",
author = "Sandrine Morel and Christina Christoffersen and Axelsen, {Lene N} and Fabrizio Montecucco and Viviane Rochemont and Frias, {Miguel A} and Francois Mach and James, {Richard W} and Naus, {Christian C} and Marc Chanson and Lampe, {Paul D} and Nielsen, {Morten S} and Nielsen, {Lars B} and Kwak, {Brenda R}",
note = "Published on behalf of the European Society of Cardiology. All rights reserved. {\circledC} The Author 2016. For permissions please email: journals.permissions@oup.com.",
year = "2016",
month = "3",
day = "1",
doi = "10.1093/cvr/cvw004",
language = "English",
volume = "109",
pages = "385--96",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "3",

}

RIS

TY - JOUR

T1 - Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43

AU - Morel, Sandrine

AU - Christoffersen, Christina

AU - Axelsen, Lene N

AU - Montecucco, Fabrizio

AU - Rochemont, Viviane

AU - Frias, Miguel A

AU - Mach, Francois

AU - James, Richard W

AU - Naus, Christian C

AU - Chanson, Marc

AU - Lampe, Paul D

AU - Nielsen, Morten S

AU - Nielsen, Lars B

AU - Kwak, Brenda R

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/cvr/cvw004

DO - 10.1093/cvr/cvw004

M3 - Journal article

VL - 109

SP - 385

EP - 396

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 3

ER -

ID: 49290238