Myocardial infarction differentially alters sphingolipid levels in plasma, erythrocytes and platelets of the rat
Magorzata Knapp
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Magorzata Z_ endzian-Piotrowska
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Agnieszka Bachnio-Zabielska
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Piotr Zabielski
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Krzysztof Kurek
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Jan Go rski
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M. Z_ endzian-Piotrowska A. Bachnio-Zabielska P. Zabielski K. Kurek J. Gorski Department of Physiology, Medical University of Biaystok
, Mickiewicza 2C, 15-089, Biaystok,
Poland
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M. Knapp (&) Department of Cardiology, Medical University of Biaystok
, Skodowskiej-Curie 24a, 15-276 Biaystok,
Poland
Three bioactive sphingolipids, namely sphingosine-1-phosphate (S1P), ceramide (CER) and sphingosine (SPH) were shown to be involved in ischemia/ reperfusion injury of the heart. S1P is a powerful cardioprotectant, CER activates apoptosis and SPH in a low dose is cardioprotective whereas in a high dose is cardiotoxic. The aim of the present study was to examine effects of experimental myocardial infarction on the level of selected sphingolipids in plasma, erythrocytes and platelets in the rat. Myocardial infarction was produced in male Wistar rats by ligation of the left coronary artery. Blood was taken from the abdominal aorta at 1, 6 and 24 h after the ligation. Plasma, erythrocytes and platelets were isolated and S1P, dihydrosphingosine-1-phosphate (DHS1P), SPH, dihydrosphingosine (DHS) and CER were quantified by means of an Agilent 6460 triple quadrupole mass spectrometer using positive ion electrospray ionization source with multiple reaction monitoring. The infarction reduced the plasma level of S1P, DHS1P, SPH and DHS but increased the level of total CER. In erythrocytes, there was a sharp elevation in the level of SPH and DHS early after the infarction and a reduction after 24 h whereas the level of S1P, DHS1P and total CER gradually increased. In platelets, the level of each of the examined compounds profoundly decreased 1 and 6 h after the infarction and partially normalized in 24 h. The results obtained clearly show that experimental heart infarction in rats produces deep changes in metabolism of sphingolipids in the plasma, platelets and erythrocytes.
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It is well documented that certain bioactive sphingolipids,
especially sphingosine-1-phosphate (S1P) and ceramide
(CER) exert powerful effects on the heart response to
experimental ischemia/reperfusion (I/R) injury.
Interestingly, each of them exerts different effects. Extracellular
S1P is a very powerful cardioprotectant. It was shown to
increase viability of isolated cardiomyocytes subjected to
hypoxia or ischemia/reperfusion [27, 48, 60]. Also, it was
reported to reduce the infarct size and left ventricular end
diastolic pressure (LVEDP) and to accelerate recovery of
the left ventricular developed pressure (LVDP) in isolated,
perfused rat and mouse hearts exposed to
ischemia/reperfusion [26, 34, 49, 55]. S1P is claimed to be the principal
mediator of ischemic pre- and post-conditioning [24, 25,
54]. It binds to the S1P receptors in the plasma membrane
and the complex activates G protein [37, 45]. This, in turn,
activates Akt kinase [16, 36, 38] and Stat3 [10, 15, 28]
which have prosurvival properties. The kinases also play a
key role in cardioprotective action of other mediators
including TNFa [20, 30]. Very recent contribution
indicates on involvement of mitochondrial S1P in
cardioprotection [18]. The main source of S1P in the plasma are
erythrocytes [9, 19, 40, 45]. Platelets and endothelial cells
also contribute to this pool of S1P [29, 51, 57]. I/R
procedure was shown to increase the level of CER in the
myocardium of rats and rabbits in vivo and in isolated,
perfused rat heart [3, 5, 12, 13, 59] and isolated
cardiomyocytes [6]. CER is claimed to strongly activate
apoptosis in the I/R heart [3, 6]. The data on effect of I/R on
behavior of sphingosine (SPH) in isolated, perfused heart
are controversial: both elevation [11] and reduction [12] in
its level was reported. SPH present in the perfusion
medium in a high dose is cardiotoxic during I/R. On the other
hand, at physiological concentration, it is cardioprotective
[56]. SPH was shown to be involved in myocardial
dysfunction resulted from microembolization of the coronary
vessels in dogs [50]. It is also suggested that SPH
contributes to a protective action of TNFa on cardiac
mitochondria [33].
The data presented above indicate that the plasma S1P
and SPH concentration may be an important factor
affecting the heart function during ischemia and I/R.
Todate, there are only two published studies available
concerning the plasma concentration of selected sphingolipids
after myocardial infarction and they concern humans. In
one study, a 50 % reduction in the total plasma
concentration of S1P and dihydrosphingosine 1-phosphate
(DHS1P) early after the infarction and in 5 days later was
reported. The concentration of SPH, CER and
dihydrosphingosine (DHS) remained stable [31]. In the other study
[44], the total plasma S1P concentration after the infarction
depended on the time after the event: it was stable at \2 h,
elevated in 2-12 h and returned to the contr (...truncated)