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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Cardiovasc+Res
2016 ; 109
(3
): 385-96
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English Wikipedia
Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating
the gap junction protein Connexin43
#MMPMID26762268
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
Cardiovasc Res
2016[Mar]; 109
(3
): 385-96
PMID26762268
show ga
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.
|Animals
[MESH]
|Apolipoproteins M
[MESH]
|Apolipoproteins/genetics
[MESH]
|Cardiotonic Agents/pharmacology
[MESH]
|Connexin 43/genetics/*metabolism
[MESH]
|Connexins/genetics/*metabolism
[MESH]
|Lipoproteins, HDL/metabolism
[MESH]
|Lysophospholipids/genetics/*metabolism
[MESH]
|Mice, Knockout
[MESH]
|Myocardial Ischemia/*metabolism
[MESH]
|Myocardial Reperfusion Injury/*prevention & control
[MESH]