Heat stress preconditioning and delayed myocardial protection: what is new? Review

Cardiovascular Research 60 (2003) 469 – 477
Heat stress preconditioning and delayed myocardial protection:
what is new?
Marie Joyeux-Faure *, Claire Arnaud, Diane Godin-Ribuot, Christophe Ribuot
Laboratoire HP2, Hypoxie Physio-Pathologies Respiratoire et Cardiovasculaire, Faculte´ de Pharmacie de Grenoble, Domaine de la Merci,
38706 La Tronche, France
Time for primary review 21 days
As other preconditioning phenomena, heat stress is able to induce a delayed myocardial protection against ischaemia-reperfusion injury
by preserving ventricular function, preventing arrhythmia occurrence and reducing cellular necrosis. The development of heat stress response
has been extensively studied in order to characterize the different steps of this form of preconditioning. It appears that chemical signals (such
as nitric oxide, reactive oxygen species (ROS)) released by sublethal hyperthermic stress trigger a complex cascade of signalling events that
include activation of protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) and culminate in increased synthesis of
inducible nitric oxide synthase, cyclooxygenase-2, antioxidant enzymes and protective proteins such as heat stress proteins (Hsps). A better
understanding of this powerful protective adaptation of the cardiomyocyte is essential for the development of clinical applications and the
design of cardioprotective pharmacological agents. The purpose of this letter is to review current information regarding the characteristics of
heat stress preconditioning compared to other forms of late preconditioning.
D 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Heat stress; Preconditioning; Myocardial ischaemia
1. Introduction
Although prevention of atherosclerosis has resulted in a
significant decrease in the incidence of acute myocardial
infarction in the past decade, it is still the most common
cause of death in man in the Western World. Thus, understanding the nature of myocardial ischaemia and elucidating
endogenous cardioprotective mechanisms in order to develop rational modes of therapy remain of primary importance.
The heart possesses a remarkable ability to adapt to stress
by changing its phenotype in a manner that renders it more
resistant to subsequent injury. This powerful adaptive phenomenon, called preconditioning, is illustrated by the fact
that a sublethal stress (such as ischaemia or heat stress (HS))
applied to the myocardium enhances its tolerance to a
subsequent ischaemic stress [1,2].
The delayed transient cardioprotection, occurring 24 – 48
h after HS, results in a significant myocardial salvage
following coronary occlusion and reperfusion [3,4]. If the
mechanism by which myocardial cells adapt to stress was
understood, design and testing of specific pharmacological
agents that activate this mechanism can hopefully follow.
In this review article, we therefore discuss in detail the
endogenous protective mechanisms occurring within the
heart during HS preconditioning, from its initiation by
different chemical signals triggering a complex cascade of
signalling events, to the mediation of cardioprotection by
many potential candidates. We also discuss how recent data
suggest that adaptation to stress represents a new direction
for myocardial protection using to our best advantage the
ability of the cell to self-protect.
2. Induction of myocardial HS preconditioning
* Corresponding author. Tel.: +33-476-637-475; fax: +33-476-637108.
E-mail address: [email protected] (M. Joyeux-Faure).
HS represents a non-pharmacological preconditioning,
such as ischaemic preconditioning or exercise. It was the
0008-6363/$ - see front matter D 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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Received 5 May 2003; received in revised form 20 August 2003; accepted 25 August 2003
M. Joyeux-Faure et al. / Cardiovascular Research 60 (2003) 469–477
first stress shown to induce the synthesis of heat stress
proteins (Hsps), in particular the inducible form Hsp70, in
the heart and other tissues [5]. It usually consists of a whole
body hyperthermia during which the rectal temperature of
the experimental animal is maintained at 42 jC for 15 min
[3]. More recently, local heating of the heart in vivo has
been proposed to prevent extracardiac sequels occurring
during whole body hyperthermia [6]. In cultured cardiomyocytes, HS is performed using an increase of ambient
temperature, inducing cellular Hsp70 expression and cytoprotection [7].
[17], are also reduced by HS preconditioning. HS is also
able to preserve mitochondrial energetic capacity and
structure against ischaemic injury, an effect potentially
dependent on the synthesis of mitochondrial Hsps [20].
Finally, HS has been shown to improve the metabolic
status of reperfused myocardium by preserving high-energy
phosphate levels [9].
3.4. Preservation of coronary endothelial function
We [21] and others [22] have observed that HS preconditioning can prevent the endothelial coronary dysfunction
induced by ischaemia reperfusion [23].
3. End-points of HS preconditioning
3.1. Preservation of left ventricular function
Currie et al. [3] were the first to show that 24 h after HS,
isolated rat hearts exhibited improved contractile recovery
upon reperfusion compared to control hearts. Since then,
this observation has been extended to the rabbit [9] and the
dog [10]. This effect seems to be age-dependent, since HSinduced improved postischaemic functional recovery is
observed only in young adult rats and disappears in aged
ones [11,12].
3.2. Antiarrhythmic effect
In the rat, prior hyperthermia reduces the incidence and
duration of ventricular arrhythmias following a short sequence of ischaemia-reperfusion, both in vivo and in vitro
[13,14]. This confirms that the antiarrhythmic effect of HS
does not involve a circulatory agent and can be explained by
protective mechanisms originating within the myocardium.
3.3. Infarct size reduction and enhanced cellular viability
The effect of HS on these end-points is of particular
clinical relevance. Donnelly et al. [4] were the first to show,
in vivo in the rat, that HS reduces infarct size induced 24
h later by a 35 min left coronary artery occlusion—120 min
reperfusion sequence. Since then, this result has been confirmed in the rabbit [15,16] and the mouse [17]. Moreover,
we have shown that HS is able to protect hypertrophied
myocardium from transgenic ((mREN-2)27) hypertensive
rats against infarction [18]. In accordance with these observations, HS is also able to enhance the viability of isolated
cardiomyocytes submitted to metabolic conditions mimicking ischaemia in vitro [7,19].
Moreover, various markers of cell injury, such as
creatine kinase [3] and lactate dehydrogenase release
4. Components of the mechanism of HS preconditioning
The delayed protection against ischaemia induced by HS
is the result of a complex cascade of cellular events
representing an archetypical response of the heart to stressful stimuli. Conceptually, it is useful to subdivide this
response into three major components: (i) the chemical
species that are generated during HS and initiate the
preconditioning (triggers), (ii) the signalling pathways that
are activated by the triggers and lead to the cardioprotection
and (iii) the molecular species that are expressed and confer
protection 24– 48 h later (mediators). These potential actors
of HS response have been identified using pharmacological
tools applied either during HS (assumed to interfere with
triggers) or at the time of ischaemia (assumed to interfere
with mediators). This approach has some limitations, in
particular, the specificity of inhibitors is often a matter of
serious concern.
4.1. Triggers of HS preconditioning
Hyperthermia results in the generation of a wide variety
of metabolites and ligands, reviewed in this section,
which trigger the development of cardioprotection by
switching the phenotype of cardiomyocytes to a defensive
one (Fig. 1).
4.1.1. Catecholamines
In the conscious rat, plasma catecholamine concentrations and myocardial noradrenaline turnover have been
shown to increase during HS [24,25]. Moreover, we have
demonstrated that a1-adrenoceptors play a role in the HS
response since antagonism by prazosin during HS abolishes
delayed resistance to myocardial infarction [26]. Taken
together, these results suggest that catecholamines could
be involved in triggering HS preconditioning.
4.1.2. Nitric oxide
The most abundant free radical in the body, nitric oxide
(NO) [27], is also able to initiate HS preconditioning.
Indeed, HS sharply increases NO production in different
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HS preconditioning can protect the myocardium against
various types of stresses [3,8], but because of its clinical
relevance, we only review in this section the aspects of
protection against ischaemia-reperfusion injury.
M. Joyeux-Faure et al. / Cardiovascular Research 60 (2003) 469–477
rat organs including the heart [28]. Furthermore, we have
recently shown that the delayed reduction in infarct size
observed in isolated rat hearts is abolished by administration
of the iNOS inhibitor L-NIL prior to HS [29].
4.1.3. Reactive oxygen species
Hyperthermia also induces the production of reactive
oxygen species (ROS), such as superoxide anion (O2 )
[30,31], which also participate in the initiation of HS
response. We have recently shown that oxidative stress
occurring upon HS can trigger preconditioning since MPG
pretreatment prevents the HS-induced infarct size reduction
in the isolated rat heart [32].
Further studies will be necessary to determine the source
and identity of the ROS responsible for initiating HS
preconditioning and to assess whether NO and ROS are
part of the same mechanism (i.e., whether the involved
reactive radical species are derived from the reaction of NO
with O2 ) or act in parallel as two independent triggers [33].
Indeed, NO is known to react rapidly with O2 to form the
peroxynitrite anion (ONOO ), which decomposes, generating various highly reactive oxidants such as the hydroxyl
radical (OH) [34]. Moreover, peroxynitrite is able to induce
nitration of structural proteins creating nitrotyrosines, an
effect with potential consequences on intracellular signalling
4.1.4. Cytokines
Plasma levels of different cytokines such as interleukin1h (IL-1h), interleukin-6, interferon-g and tumor necrosis
factor (TNF) are also increased following hyperthermia
[37]. Moreover, HS-induced cardioprotection is abolished
by administration of neutralising antibodies to IL-1h and
TNF-a before HS [38]. ROS generation during hyperthermia has been shown to increase myocardial IL-1h and TNFa levels [39], leading to rapid activation and nuclear
translocation of the transcription factor nuclear factor-nB
(NF-nB) [38,40]. However, the participation of NF-nB in
the HS response remains to be investigated.
4.1.5. Heme oxygenase-1 pathway
Heme oxygenase-1 (HO-1, also regarded as Hsp32),
whose expression is markedly increased 4 – 16 h after HS
[41,42], is an HO isoform which degrades intracellular
heme into carbon monoxide, an important signal messenger
regulating cardiovascular function, and bilirubin, a potent
antioxidant. Since HS-induced cardioprotection can be
abolished by treatment with an HO inhibitor prior to
hyperthermia, a role for the HO-1 pathway in triggering
HS preconditioning can be evoked [42].
HS is also able to activate capsaicin-sensitive sensory
nerves and stimulate the release of neurotransmitters including calcitonin gene-related peptide (CGRP), which is in-
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Fig. 1. Hypothetical representation of cellular events thought to occur following heat stress preconditioning. CO: carbon monoxide; COX-2: cyclooxygenase-2;
DAG: diacylglycerol; HO-1: hemeoxygenase-1; HSF: heat shock factor; Hsp: heat stress protein; KATP channel: ATP-sensitive potassium channel; MAPK:
mitogen-activated protein kinase; NO: nitric oxide; iNOS: inducible nitric oxide synthase; NF-nB: nuclear factor-nB; PIP2: phosphatidylinositoldiphosphate;
PLC: phospholipase C; PKC: protein kinase C; ROS: reactive oxygen species.
M. Joyeux-Faure et al. / Cardiovascular Research 60 (2003) 469–477
volved in HS-induced cardioprotection [43,44]. Since
delayed cardioprotection afforded by pharmacological preconditioning has been shown to be triggered by CGRP via
activation of the HO-1 pathway [45], this might also be the
case for HS-induced cardioprotection, although this hypothesis remains to be verified.
4.1.6. Opioids
Recent data in rats indicate that activation of y1-opioid
receptors is also involved in triggering the HS response,
since delayed cardioprotection is abolished by the opiate
receptor antagonist naloxone when administered before
hyperthermia [46]. Further studies using knock-out animals for y1-opioid receptors are needed to confirm this
In exploring the signalling pathways of HS preconditioning, we have shown that HS-induced myocardial ischaemic
tolerance in the rat was abolished by the p38 MAPK
inhibitor SB 203580 administered prior to hyperthermia
[56]. This was also observed in the mouse [17]. However,
we and others were unable to demonstrate a p38 MAPK
phosphorylation after HS [17,50,56]. Further investigations,
with knocked-out animals or more specific pharmacological
agents, are required to elucidate the precise role of various
MAPK families in HS preconditioning and the separate or
potentially coupled transduction pathways in which they are
involved. In particular, MAPKs could represent potential
downstream targets of PKC-dependent signalling mechanisms [57,58].
The stimuli previously cited trigger HS preconditioning
by activating a complex cascade of signalling events that
ultimately result in increased transcription of cardioprotective genes. Over the last years, the exploration of these
signalling pathways has been undertaken and some key
steps have been identified (Fig. 1).
4.2.1. Phospholipase C and protein kinase C
Intracellular 1,4,5-inositol triphosphate is released by HS
[47], an effect antagonised by phospholipase C inhibition.
Activation of phospholipase C also leads to diacylglycerol
release and protein kinase C (PKC) activation. We have
indeed demonstrated that PKC inhibition by chelerythrine
prior to HS abolishes the cardioprotection induced 24 h later
in the isolated rat heart [48], a finding in accordance with an
in vivo study [49]. Moreover, recent observations suggest an
important role for the epsilon isoform of PKC in this
cardioprotective mechanism [50], which can be activated
by NO [51,52]. Since we have shown that iNOS-produced
NO can trigger HS preconditioning [29], we can postulate
that NO production could be responsible for PKC activation
upon HS, a hypothesis that remains to be confirmed.
4.2.2. Protein tyrosine kinases
We have reported that tyrosine kinases did not appear to
be involved in HS preconditioning since inhibition by
genistein prior to hyperthermia did not affect cardioprotection induced 24 h later in the isolated rat heart [48].
However, this remains to be confirmed since HS has been
shown to activate c-Src tyrosine kinases in fibroblasts [53].
4.2.3. Mitogen-activated protein kinases
In response to different stresses including HS, p38
mitogen-activated protein kinase (MAPK) is activated
through dual phosphorylation on Thr-180 and Tyr-182
residues [54]. As shown by in vitro assays [55], two p38
MAPK substrates (MAPKAPK-2 and -3), phosphorylate
Hsp27, a potential mediator of HS preconditioning.
HS preconditioning requires increased synthesis of new
proteins to induce cardioprotection. Indeed, the time course
of enhanced tolerance to ischaemia, which requires 24– 48
h to develop and lasts for 3– 4 days [59], is also consistent
with the synthesis and subsequent degradation of cardioprotective proteins. Several proteins, which are reviewed in
this section, have been proposed as potential mediators of
the protection afforded by HS preconditioning (Fig. 1).
Most of the mediators cited seem to play a role in the final
steps of the signalling pathway associated with the HS
response. But at least two of them, the antioxidant enzymes
and changes in calcium homeostasis, could represent potential final end-effectors in the mediation of cardioprotection
induced by HS preconditioning.
4.3.1. Heat stress proteins
HS induces an increase in expression of various Hsps
(Hsp110, Hsp90, Hsp70 and small molecular mass Hsps)
that could all be responsible for protection against myocardial ischaemia [60]. In particular, members of the Hsp70
family have been shown to repair or remove denatured
proteins within the cell, leading to restoration of cell
function during recovery from stress [61]. The evidence
suggesting Hsp70 as the primary mediator of cardioprotection was brought about by the observation of a direct
correlation between the amount of Hsp70 induced following
HS and the degree of myocardial protection in the rat [62]
and in the rabbit [63]. Further evidence that Hsp70 plays a
direct role in the protection from myocardial ischaemiareperfusion injury has been obtained using transfected
cultured cells [7] [64] or animals [65 –67] overexpressing
the Hsp70 gene.
Although these studies demonstrate the cytoprotective
effects of Hsps, the direct relationship between Hsp synthesis and HS-induced cardioprotection remains controversial.
Indeed, several recent studies indicate that the quantitative
accumulation of Hsp70 is unlikely to be the sole determinant of HS-induced cardioprotection since it occurs independently of the level of Hsp70 expression [17,49,68]. Also,
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4.3. Mediators of HS preconditioning
4.2. Signalling aspects of HS preconditioning
M. Joyeux-Faure et al. / Cardiovascular Research 60 (2003) 469–477
pathway, potentially through MAPK activation [83,84],
although NO [85] and COX-2 [86] are also able to activate
these channels.
Thus, further investigations are required to confirm the
identity of KATP channels involved in HS preconditioning
(i.e., sarcolemmal versus mitochondrial) and also to determine how they are opened and how their opening confers
4.3.2. Nitric oxide
We have provided the first demonstration that iNOSderived NO is a mediator of HS preconditioning, since the
infarct-sparing effect seen in vivo in the rat is abolished by
two NOS inhibitors, L-NAME and 1400W, when given
before ischaemia [70]. Concurrently, we have shown a
strong increase in iNOS protein expression 24 h after HS.
Activation of the iNOS gene transcription by preconditioning has been linked to various upstream components (see
Section 4.1.) such as NO itself [71] or NF-nB [72].
4.3.6. Antioxidant enzymes
Antioxidant enzymes could represent potential final endeffectors in the mediation of cardioprotection induced by HS
preconditioning. In agreement with Currie et al. [3], we have
observed in the rat that HS increases endogenous myocardial catalase activity 24 h later [14]. This antioxidant
enzyme appears to be involved in mediating HS-induced
cardioprotection, since administration of a catalase inhibitor
(3-aminotriazole) prior to ischaemia-reperfusion abolishes
the antiarrhythmic effect [14], the improvement in functional recovery [87] and the infarct-sparing effect [88].
Another antioxidant enzyme that can mediate HS preconditioning is manganese superoxide dismutase (MnSOD), whose mRNA and protein have been shown to
be significantly increased in rat cardiomyocytes 24 h after
HS [59,89,90]. Inhibition of Mn-SOD expression by
treatment with antisense oligodeoxyribonucleotides completely abolishes the HS-induced tolerance to hypoxiareoxygenation [89].
4.3.3. Cyclooxygenase-2
Cyclooxygenase-2 (COX-2) catalyses the first two steps
in the biosynthesis of prostaglandins (PGs) from arachidonic
acid [73]. We were the first to observe that COX-2 activity
is necessary during ischaemia-reperfusion to mediate cardioprotection, since the protective effect of HS is abolished
by two different COX-2 inhibitors (celecoxib and NS-398)
when given before ischaemia [74]. We have also shown a
marked increase in myocardial COX-2 protein expression
24 h after HS.
COX-2 can be activated by NO [75], but this remains to
be investigated in the context of the HS response.
4.3.4. Endogenous cannabinoids
The first evidence of the implication of endogenous
cannabinoids in mediating HS-induced cardioprotection has
recently been provided by our group. Thus, in isolated rat
hearts, perfusion by a CB2 receptor antagonist (SR 144528),
but not by a CB1 receptor antagonist (SR 141716), abolishes
the infarct size-reducing effect of HS [76].
The endocannabinoid system, which is related to NO
production [77], appears to be involved in the regulation of
many cardiovascular functions, with endocannabinoids being able to induce hypotensive and bradycardic effects (for a
review see Ref. [78]).
4.3.7. Calcium homeostasis
Changes in calcium homeostasis also appear to play a role
in the mediation of HS response, being a potential final
effector of the cytoprotection. Indeed, HS leads to significantly lower postischaemic mitochondrial calcium content
and attenuates submaximal calcium paradox in the isolated
rabbit heart [91]. HS-induced myocardial protection is also
associated with enhancement of sarcoplasmic reticulum
Ca2 +-pump activity that maintains net Ca2 +-uptake by
counterbalancing the enhanced Ca2 +-release channel activity
produced by ischaemia-reperfusion [92]. Specific studies,
measuring intracellular calcium concentration and fluxes, are
needed to fully elucidate the exact role of calcium ions in
cardioprotection conferred by HS preconditioning.
5. Comparison with other forms of preconditioning
4.3.5. KATP channels
The opening of ATP-sensitive potassium (KATP) channels appears to play a role in mediating HS preconditioning
in the rat [79] and in the rabbit [80,81]. In particular, it has
been shown that the mitochondrial KATP channel blocker
5-hydroxydecanoate is able to abolish the HS-induced
PKC activation is known to induce the opening of these
channels [82]. We can thus presume that KATP channel
opening induced by HS could depend on a PKC signalling
The delayed cardioprotection, induced 24 – 48 h following
HS, appears to be similar to that seen with other forms of
preconditioning, which can be broadly classified as nonpharmacological (HS, ischaemia, rapid cardiac pacing and
exercise) and pharmacological (endotoxin, cytokines, ROS,
NO donors, adenosine receptor agonists, monophosphoryl
lipid A and analogs, opioid agonists,. . .) (for a review see
Ref. [33]). Amongst them, ischaemic preconditioning has
been extensively studied and appears to induce two distinct
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we and others have shown that the infarct size-reducing
effect of HS is abolished by a1-adrenoceptors blockers [26]
and by PKC [48,69] and MAPK inhibitors [17,56], without
concomitant changes in Hsp70 induction. These observations reinforce the hypothesis that several cytoprotective
mechanisms are involved in HS preconditioning. Finally,
the main protective role of chaperoning Hsps could thus be
to bind and protect other potential end-effectors.
M. Joyeux-Faure et al. / Cardiovascular Research 60 (2003) 469–477
6. HS preconditioning and potential therapeutic benefits
The protective HS preconditioning phenomenon is likely
to benefit patients suffering repeated ischaemic episodes or
at reperfusion following ischaemia. As discussed below,
myocardial protection could be obtained either by mimicking HS preconditioning through pharmacological agents or
by direct application.
6.1. Pharmacological preconditioning
Therapeutic approaches mimicking HS preconditioning
seem feasible today. As previously described, NO and
KATP potassium channels are some important actors of
the preconditioning phenomenon. A sustained cardioprotection similar to that afforded by HS preconditioning can
be induced pharmacologically with NO donors and KATP
channel openers. Thus, nicorandil, which possesses both
properties, is an effective anti-anginal agent that can
protect the heart in a preconditioning fashion [98]. Various
pharmaceutical companies are currently investigating KATP
channel openers designed to mimic preconditioning.
Delayed preconditioning effects of volatile anaesthetics
and opioids are also under clinical investigation [99].
Another pharmacological preconditioning agent is adenosine, which is currently used in cardioplegic solutions
during cardiopulmonary bypass [100]. However, the clinical use of this agent is only related to its acute cardioprotective effects, and a possible application for its delayed
cardioprotective properties remains to be described.
Exploiting the cytoprotective properties of Hsps could
also represent a future therapeutic approach. In rodent
myocardium, Hsp70 gene transfection is achieved through
intracoronary or intravenous injection or by direct injection
of naked plasmid or virus liposome. The development of
these techniques for clinical use has therapeutic potential
[101]. A recently introduced cytoprotective hydroxylamine
derivative, bimoclomol, facilitates the formation of all
major Hsps, in particular Hsp70, in eukaryotic cells by
inducing or amplifying expression of their genes [102].
This compound has been shown to increase cardiomyocyte
survival [103] and to protect the rat heart against ischaemia-reperfusion when orally administered 6 h earlier [104].
Interestingly, the beneficial effects of bimoclomol appear
only under stress conditions and depend at least in part on
its Hsp-coinducer property. This nontoxic drug, which is
under Phase II clinical trials, has tremendous therapeutic
potential [102,105].
6.2. Performing HS
HS preconditioning can also be directly applied in order
to induce protection in specific situations such as transplantation and grafting. In the rat, prior HS has been shown to
protect the heart by increasing functional recovery and
decreasing cellular necrosis after a cold ischaemia in a
protocol mimicking that of heart preservation for transplantation [106]. Similarly, when rat skeletal myoblasts and
cardiomyocytes are grafted into the heart for cardiac repair,
graft cell survival is enhanced by prior HS [107,108]. Thus,
HS could be useful in graft cell survival and in heart
preservation protocols for transplantation.
In conclusion, a better understanding of endogenous
cardioprotective mechanisms based on experimental investigation could lead to carefully conducted clinical studies
comparing the relative effectiveness of this protection with
more conventional therapeutic strategies. The identification
of the cellular basis of the HS phenomenon should provide a
conceptual framework for developing novel therapeutic
strategies aimed at mimicking its cardioprotective effects
with pharmacological agents or genetic approaches that can
maintain the heart in a sustained or chronic defensive state.
Although only few potential pharmacological approaches to
protection seem feasible at present, we can hope that they will
be rapidly developed in the upcoming years, leading to
additional myocardial salvage of the reperfused myocardium.
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phases of protection: an early phase (lasting for 2 –3 h),
followed by a delayed one (after 24 –96 h) [2].
As for HS, delayed ischaemic preconditioning protects
the myocardium against infarction [93], stunning [94],
arrhythmias [95] and endothelial dysfunction [96]. The
other forms of preconditioning are also able to induce an
infarct-sparing effect.
Although the signal transduction pathways underlying all
these preconditionings are largely unknown, recent data
suggest similarities and common key actors have been
identified. There is now convincing evidence that NO and
ROS serve as chemical signals triggering development of
the preconditioning phenomenon, that PKC is essential for
its genesis and that several proteins, such as iNOS, COX-2,
antioxidant enzymes, Hsps and KATP channels, are possible
mediators of the cytoprotection induced. The time course of
delayed cardioprotection induced by other forms of preconditioning is also suggestive of a mechanism involving new
protein synthesis. However, HS preconditioning only induces delayed cardioprotection [97], suggesting that it is
exclusively dependent on new protein synthesis, a characteristic which could ultimately represent an advantage for
clinical use.
The shift of the heart to a defensive phenotype is a
complex response requiring the coordinated activation of
multiple genes. Unravelling the complexity of this polygenic phenotypic change will likely be a challenge for years to
come [33].
M. Joyeux-Faure et al. / Cardiovascular Research 60 (2003) 469–477
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