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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 6, November/December 2016
384
AFRICA
We are therefore confronted with two sets of disparate
observations: FTY720 administration limited IFS, yet
simultaneously suppressed functional recovery. Such a
dissociation between changes in IFS and changes in functional
recovery, as observed here, have been reported by us
44,74,75
and
others.
76-78
Although it is unexpected, it is therefore not without
precedent or possible explanation through combination of the
diverse effects of FTY720 on the heart.
FTY720, both unphosphorylated and phosphorylated,
activates several cardioprotective pathways, possibly including
components such as protein kinase A (PKA), protein kinase G
(PKG), protein kinase C (PKC), PKB/Akt, ERK p42/p44 and
Pak1.
21,22,30-32,63
The robust activation of these pathways culminated
in protection of the heart tissue against injury and cell death,
thereby explaining the reduction in IFS associated with the
administration of 1
µ
M FTY720 at the onset of reperfusion,
as well as 2.5
µ
M both prior to ischaemia and at the onset of
reperfusion. The effect of the pre-ischaemic administration
of FTY720 on IFS may be due to the contribution of PP2A
activation, which at this dose and during ischaemia and the
onset of reperfusion, opposes cardioprotective signalling
by de-phosphorylating some of the proteins involved in the
mediation of protection.
Theoretically, possible targets for PP2Aunder these conditions
include PKC, PKA, PKB/Akt and ERK p42/p44.
79
Work done in
our laboratory has also implicated PP2A as a negative regulator
of PKB/Akt at the onset of reperfusion (unpublished data).
These results highlight the importance of the time point of
intervention in determining the outcome of I/R. Simultaneously
however, FTY720, especially at the higher dose of 2.5
µ
M,
exerted a potent effect on heart rate and contractility of the
heart by contributing to an increase in membrane potential
and reducing the availability of Ca
2+
at the myofibrils of the
cardiomyocytes. The result of this is a major and profound
reduction in cardiac function during reperfusion.
The prescribed dose of FTY720 for recurring MS is 0.5 mg
once daily. This translates into a blood concentration of less
than 0.5 ng/ml after 96 hours in renal transplant recipients,
80,81
which is less than 1.45 nM. Even though FTY720 in these
small concentration ranges exerted a very small and transient
effect on heart rate in patients,
80,82
it is still much lower than the
concentrations we used. Our study therefore does not address
concerns with regard to the current FTY720 treatment regime.
Our results are however of potential importance in the context
of anticancer therapy, where the administration of relatively high
doses of FTY720 becomes relevant, as well as the potential use
of FTY720 to limit the development of myocardial I/R injury.
62
Conclusion
We have shown that the effects of acute FTY720 treatment
are dependent on both the timing of the intervention, as well
as the dose at which it is administered. Although FTY720 has
the ability to limit IFS, acute pre-ischaemic administration was
much less beneficial than reperfusion administration. Increasing
the concentration of FTY720, although still reducing IFS
development, exerted a profoundly negative effect on post-
ischaemic heart function. More work is needed to describe the
mechanism by which acute FTY720 administration at these
concentrations exerts its effects on cardiac function, especially
in the context of its effects on kinase/phosphatase signalling and
Ca
2+
handling.
This work was financially supported by the Harry Crossley Foundation,
the Medical Research Council of South Africa, and the National Research
Foundation of South Africa.
References
1.
World Health Organisation. Global status report on noncommunicable
diseases 2010: description of global burden of NCDs, their risk factors
and determinants, 2011 (ISBN: 978 924 156422 9).
2.
Sliwa K, Wilkinson D, Hansen C, Ntyintyane L, Tibazarwa K, Becker
A, Stewart S. Spectrum of heart disease and risk factors in a black urban
population in South Africa (the Heart of Soweto Study): a cohort study.
Lancet
2008;
371
: 915–922 (PMID: 18342686).
3.
Onen CL. Epidemiology of ischaemic heart disease in sub-Saharan
Africa.
Cardiovasc J Afr
2013;
24
: 34–42 (PMID: 23612951).
4.
Statistics South Africa. Mortality and causes of death in South Africa,
2013: Findings from death notification. Pretoria: Statistics South Africa;
2014.
5.
Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M,
Flaxman A,
et al
. The global burden of ischemic heart disease in 1990
and 2010: The global burden of disease 2010 study.
Circulation
2014;
129
: 1493–1501 (PMID: 24573351).
6.
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V,
et
al
. Global and regional mortality from 235 causes of death for 20 age
groups in 1990 and 2010: a systematic analysis for the Global Burden of
Disease Study 2010.
Lancet
2012;
380
: 2095–2128 (PMID: 23245604).
7.
Murray CJL, Lopez AD. Alternative projections of mortality and
disability by cause 1990–2020: Global Burden of Disease Study.
Lancet
1997;
349
: 1498–1504 (PMID: 9167458).
8.
Mathers CD, Loncar D. Projections of Global Mortality and Burden
of Disease from 2002 to 2030.
PLoS Med
2006;
3
: 2011–2030 (PMID:
17132052).
9.
Ting HH, Yang EH, Rihal CS. Narrative review: Reperfusion strategies
for ST-segment elevation myocardial infarction.
Ann Intern Med
2006;
145
: 610–617 (PMID: 17043342).
10. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute
ST-segment elevation myocardial infarction: a comprehensive review
of contemporary management options.
J Am Coll Cardiol
2007;
50
:
917–929 (PMID: 17765117).
11. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a
delay of lethal cell injury in ischemic myocardium.
Circulation
1986;
74
:
1124–1136 (PMID: 3769170).
12. Vinten-Johansen J, Zhao Z-Q, Zatta AJ, Kin H, Halkos ME, Kerendi
F. Postconditioning: A new link in nature’s armor against myocardial
ischemia-reperfusion injury.
Basic Res Cardiol
2005;
100
(4): 295–310
(PMID: 15793629).
13. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury.
N Engl J
Med
2007;
357
: 1121–1135 (PMID: 17855673).
14. Hausenloy DJ, Yellon DM. New directions for protecting the heart
against ischaemia–reperfusion injury: targeting the Reperfusion Injury
Salvage Kinase (RISK) pathway.
Cardiovasc Res
2004;
61
: 448–460
(PMID: 14962476).
15. Lecour S. Activation of the protective Survivor Activating Factor
Enhancement (SAFE) pathway against reperfusion injury: Does it go
beyond the RISK pathway?
J Mol Cell Cardiol
2009;
47
: 32–40 (PMID:
19344728).
16. Yang X, Cohen MV, Downey JM. Mechanism of protection by early