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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016
AFRICA
375
The differential effects of FTY720 on functional recovery
and infarct size following myocardial ischaemia/
reperfusion
Derick van Vuuren, Erna Marais, Sonia Genade, Amanda Lochner
Abstract
Aim:
The aim of this study was to evaluate the effects of
the sphingosine analogue, FTY720 (Fingolimod), on the
outcomes of myocardial ischaemia/reperfusion (I/R) injury.
Methods:
Two concentrations of FTY720 (1 or 2.5
µ
M)
were administered either prior to (PreFTY), or following
(PostFTY) 20 minutes’ global (GI) or 35 minutes’ regional
ischaemia (RI) in the isolated, perfused, working rat heart.
Functional recovery during reperfusion was assessed follow-
ing both models of ischaemia, while infarct size (IFS) was
determined following RI.
Results:
FTY720 at 1
µ
M exerted no effect on functional
recovery, while 2.5
µ
M significantly impaired aortic output
(AO) recovery when administered prior to GI (% recovery:
control: 33.88
±
6.12% vs PreFTY: 0%,
n
=
6–10;
p
<
0.001),
as well as before and after RI (% recovery: control: 27.86
±
13.22% vs PreFTY: 0.62%;
p
<
0.05; and PostFTY: 2.08%;
p
=
0.0585,
n
=
6). FTY720 at 1
µ
M administered during reperfu-
sion reduced IFS [% of area at risk (AAR): control: 39.89
±
3.93% vs PostFTY: 26.56
±
4.32%,
n
=
6–8;
p
<
0.05), while 2.5
µ
M FTY720 reduced IFS irrespective of the time of adminis-
tration (% of AAR: control: 39.89
±
3.93% vs PreFTY: 29.97
±
1.03%; and PostFTY: 30.45
±
2.16%,
n
=
6;
p
<
0.05).
Conclusion:
FTY720 exerted divergent outcomes on function
and tissue survival depending on the concentration adminis-
tered, as well as the timing of administration.
Keywords:
functional recovery, FTY720, ischaemia/reperfusion
injury, infarct size, myocardial, working heart perfusion
Submitted 28/10/15, accepted 30/3/16
Cardiovasc J Afr
2016;
27
: 375–386
www.cvja.co.zaDOI: 10.5830/CVJA-2016-039
In 2008 the WHO reported that non-communicable diseases
(NCDs), including cardiovascular disease, are the leading causes
of death globally.
1
South Africa, as well as the broader African
region, is no exception, with recent research indicating the
prevalence of NCDs and cardiovascular disease.
2-5
Ischaemic
heart disease has been identified as a major contributor to
global morbidity and mortality rates
6
in a trend set to continue,
irrespective of affluence.
7,8
The current clinical approach to myocardial ischaemia is to
limit the duration of ischaemia by re-establishing perfusion of
the affected tissue as fast as possible.
9,10
The first description of
ischaemic preconditioning
11
however also exposed the innate ability
of the heart to increase its resistance to ischaemia/reperfusion
(I/R) injury. The fact that interventions can also be applied in
conjunction with reperfusion to enhance the beneficial effects of
reperfusion proves that (1) a degree of damage is imparted by
reperfusion
per se
, a phenomenon that is known as reperfusion
injury;
12,13
and (2) the modulation of intracellular events inside the
cardiomyocyte can protect the heart over and above the beneficial
effect of rapid reperfusion.
13
This is known as cardioprotection.
Research has revealed several well-defined intracellular
signalling pathways associated with cardioprotection, including
the reperfusion injury salvage kinase (RISK)
14
and survivor
activating factor enhancement (SAFE)
15
pathways. These, and
others, havebeenextensively reviewedelsewhere.
16,17
Twomolecules
that have been implicated in the mediation of cardioprotection is
the sphingolipid, sphingosine and its phosphorylated metabolite,
sphingosine-1-phosphate (S1P).
18,19
It has been shown that
sphingosine and S1P can elicit cardioprotection through the
activation of several of the known cardioprotective pathways.
20-24
FTY720 (also known as Fingolimod), a derivative of a
metabolite of a fungal species that has long been associated
with medicinal effects in Chinese folk medicine,
25
is a structural
analogue of sphingosine. As such, it is metabolised in a similar
fashion to sphingosine in that; it easily traverses the cell
membrane to be phosphorylated intracellularly by sphingosine
kinase 2 (SK2). The phosphorylated FTY720 (P-FTY720)
then exits the cell to bind to a sphingosine-1-phosphate (S1P)
receptor. Five receptors have been identified, of which four can
interact with P-FTY720: S1P1, 3, 4 and 5.
26,27
Since S1P and sphingosine have been associated with a
reduction in the myocardial damage caused by I/R,
20-14
several
researchers have turned their attention to the potential benefits
of FTY720 within this setting, with mixed success. Especially
three endpoints have been addressed by the current body of
research: rhythmicity, cell death/survival and functional ability
following I/R. FTY720 appears to exert an effect on rhythmicity,
however, the results obtained are controversial. Egom and
co-workers
28
reported that FTY270 reduced the occurrence of
rhythmic disturbances post-I/R in an
ex vivo
rat heart, as well
as in a sino-atrial node preparation. These beneficial effects
were however absent in an
in vivo
rat model, where FTY720
administered during reperfusion proved detrimental due to an
increased occurrence of tachycardia and ventricular fibrillation.
29
Similarly, the effects of FTY720 on cell death are controversial;
some researchers have reported that it decreases infarct size
Division of Medical Physiology, Department of Biomedical
Sciences, Faculty of Medicine and Health Sciences,
Stellenbosch University, Tygerberg, South Africa
Derick van Vuuren, PhD,
dvvuuren@sun.ac.zaErna Marais, PhD
Sonia Genade, BSc
Amanda Lochner, PhD