Protection of the ischaemic heart : investigations into the phenomenon of ischaemic preconditioning
Date
2009-02
Authors
Lochner, A.
Marais, E.
Genade, S.
Huisamen, B.
Du Toit, E. F.
Moolman, J. A.
Journal Title
Journal ISSN
Volume Title
Publisher
Clinics Cardiv Publishing
Abstract
Exposure of the heart to one or more short episodes of
ischaemia/reperfusion protects the heart against a subsequent
prolonged period of ischaemia, as evidenced by a
reduction in infarct size and an improvement in functional
recovery during reperfusion. Elucidation of the mechanism
of this endogenous protection could lead to the development
of pharmacological mimetics to be used in the clinical setting.
The aim of our studies was therefore to gain more information
regarding the mechanism of ischaemic preconditioning,
using the isolated perfused working rat heart as model.
A preconditioning protocol of 1 × 5 or 3 × 5 min of ischaemia,
interspersed with 5 min of reperfusion was found
to protect hearts exposed to 25 min of global ischaemia or
35–45 min of regional ischaemia. These models were used
throughout our studies.
In view of the release of catecholamines by ischaemic
tissue, our first aim was to evaluate the role of the alphaadrenergic
receptor in ischaemic preconditioning. However,
using a multi-cycle ischaemic preconditioning protocol, we
could not find any evidence for alpha-1 adrenergic or PKC
activation in the mechanism of preconditioning. Cyclic
increases in the tissue cyclic nucleotides, cAMP and cGMP
were found, however, to occur during a multi-cycle preconditioning
protocol, suggesting roles for the beta-adrenergic
signalling pathway and nitric oxide (NO) as triggers of
cardioprotection. This was substantiated by the findings that
(1) administration of the beta-adrenergic agonist, isoproterenol,
or the NO donors SNAP or SNP before sustained
ischaemia also elicited cardioprotection similar to ischaemic
preconditioning; (2) beta-adrenergic blockade or nitric
oxide synthase inhibition during an ischaemic preconditioning
protocol abolished protection. Effectors downstream of
cAMP, such as p38MAPK and CREB, were also demonstrated
to be involved in the triggering process.
Our next step was to evaluate intracellular signalling
during sustained ischaemia and reperfusion. Our results
showed that ischaemic preconditioned-induced cardioprotection
was associated with a significant reduction in tissue
cAMP, attenuation of p38MAPK activation and increased
tissue cGMP levels and HSP27 activation, compared to
non-preconditioned hearts. The role of the stress kinase
p38MAPK was further investigated by using the inhibitor
SB203580. Our results suggested that injury by necrosis and
apoptosis share activation of p38MAPK as a common signal
transduction pathway and that pharmacological targeting of
this kinase offers a tenable option to manipulate both these
processes during ischaemia/reperfusion injury.
Description
The original publication is available at http://www.cvja.co.za/
Bibliography
Bibliography
Keywords
Heart disease, Reperfusion, Mimetics, Catecholamines
Citation
Lochner, A. et al. 2009. Protection of the ischaemic heart: investigations into the phenomenon of ischaemic preconditioning. Cardiovascular Journal of Africa, 20(1), 43-51.