© 2000 American Heart Association, Inc.
Review |
The Late Phase of Preconditioning
From the Division of Cardiology, University of Louisville and Jewish Hospital Heart and Lung Institute, Louisville, Ky.
Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail rbolli{at}louisville.edu
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Abstract |
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 Top Abstract IntroductionClassification of Late PCComponents of the Mechanism...Triggers (or Initiators) of...The Signaling Pathway of...ConclusionsReferences |
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Abstract—Unlike the early phase of preconditioning (PC), which lasts 2 to 3 hours and protects against infarction but not against stunning, the late phase of PC lasts 3 to 4 days and protects against both infarction and stunning, suggesting that it may have greater clinical relevance. It is now clear that late PC is a polygenic phenomenon that requires the simultaneous activation of multiple stress-responsive genes. Chemical signals released by a sublethal ischemic stress (such as NO, reactive oxygen species, and adenosine) trigger a complex cascade of signaling events that includes the activation of protein kinase C, Src protein tyrosine kinases, and nuclear factor
B and culminates in increased synthesis
of inducible NO synthase, cyclooxygenase-2, aldose reductase, Mn
superoxide dismutase, and probably other cardioprotective proteins. An
analogous sequence of events can be triggered by a variety of stimuli,
such as heat stress, exercise, and cytokines. Thus, late PC appears to
be a universal response of the heart to stress in general. Importantly,
the cardioprotective effects of late PC can be reproduced
pharmacologically with clinically relevant agents (eg, NO donors,
adenosine receptor agonists, endotoxin derivatives, or opioid receptor
agonists), suggesting that this phenomenon might be exploited for
therapeutic purposes. The purpose of this review is to summarize
current information regarding the pathophysiology and mechanism of late
PC.
Key Words: myocardial ischemia • myocardial reperfusion • nitric oxide • cyclooxygenase • aldose reductase
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Introduction |
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TopAbstractIntroductionClassification of Late PCComponents of the Mechanism...Triggers (or Initiators) of...The Signaling Pathway of...ConclusionsReferences |
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The heart possesses a remarkable ability to adapt to stress by changing its phenotype in a manner that makes it more resistant to injury. The power of this phenotypic plasticity is perhaps illustrated most eloquently by the phenomenon of ischemic preconditioning (PC), the process whereby a sublethal ischemic stress enhances the tolerance of the myocardium to a subsequent ischemic stress. Originally described as an immediate adaptation of the heart to brief coronary occlusions,1 ischemic PC was subsequently found to be a biphasic phenomenon, with an early phase of protection that develops within minutes from the initial ischemic insult and lasts 2 to 3 hours and a late (or delayed) phase that becomes apparent 12 to 24 hours later and lasts 3 to 4 days.2 3 Unlike the early phase, the late phase of ischemic PC protects not only against myocardial infarction but also against myocardial stunning.4 Because of this, and because of its sustained duration, considerable interest has recently focused on the late phase and on its clinical relevance. If the mechanism of this adaptive metamorphosis is elucidated, then it should be possible to exploit it to protect the ischemic myocardium in patients.
The recognition that the heart shifts to a preconditioned phenotype upon exposure to stress has undoubtedly been one of the major advances in the field of myocardial ischemia. In the past few years, much has been learned regarding the intricate signaling pathways and genetic changes that underlie this defensive adaptation. The purpose of the present essay is to succinctly summarize current information regarding the pathophysiology and mechanism of late PC. Although this review will focus solely on the heart, it should be noted that late PC has also been observed in other organs (eg, brain, intestine, and liver), suggesting that this is a universal mechanism whereby tissues protect themselves from an impending threat.
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Classification of Late PC |
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TopAbstractIntroductionClassification of Late PCComponents of the Mechanism...Triggers (or Initiators) of...The Signaling Pathway of...ConclusionsReferences |
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Late PC can be categorized on the basis of the stimulus that elicits this response and of the end point examined (Table 1
). Delayed protection against myocardial
ischemia/reperfusion injury can be induced by a wide variety of
stimuli, which can be broadly classified as nonpharmacological and
pharmacological. Besides ischemia, the former include heat
stress,5 rapid ventricular
pacing,6 and
exercise.7 The latter consist
of naturally occurring—and often noxious—agents (eg,
endotoxin,8
interleukin-1,9 tumor
necrosis factor-
[TNF-],10
TNF-ß,11 leukemia
inhibitory factor,11
reactive oxygen species
[ROS]12 ) and of clinically
applicable drugs (NO-releasing
agents,13 adenosine receptor
agonists,14 endotoxin
derivatives such as monophosphoryl lipid A
[MLA]15 and its analog
RC-552,16 and opioid
receptor agonists17 ). Most
of these forms of late PC have been shown to protect against lethal
ischemia/reperfusion injury (infarction), and at least some have been
demonstrated to protect against reversible postischemic dysfunction
(stunning),18
arrhythmias,6 and endothelial
dysfunction19
(Table 1). This classification is not purely
phenomenological, because recent evidence suggests the existence of
mechanistic differences among the various forms of late PC outlined in
Table 1 (eg, adenosine and ATP-sensitive potassium
[KATP] channels play an obligatory role in
ischemia-induced late PC against
infarction14 20 21 22 23 24 25 26
but not against
stunning18 24 26 27 ).
Therefore, to avoid inappropriate generalizations, it is important to
define (using the nature of the stimulus and of the protective effect)
which specific form of late PC is being examined (eg, NO donor–induced
late PC against stunning; ischemia-induced late PC against infarction,
etc)
(Table 1).
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Components of the Mechanism of Late PC |
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TopAbstractIntroductionClassification of Late PCComponents of the Mechanism...Triggers (or Initiators) of...The Signaling Pathway of...ConclusionsReferences |
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Ischemia-induced late PC is the result of a complex cascade of cellular events that represents an archetypical response of the heart to diverse stressful stimuli (Figure
).
Conceptually, it is useful to subdivide this cascade into 3 major
components: (1) the molecular species that are generated during the
first ischemic challenge and are responsible for initiating the
adaptation ("triggers" of late PC), (2) the molecular species that
are expressed in the heart 24 to 72 hours later and are responsible for
conferring protection during the second ischemic challenge
("mediators" of late PC), and (3) the signaling pathways that are
activated by the triggers and culminate in the expression of the
mediators
(Figure).
It should be noted that both triggers and signaling pathways operate
soon after the PC stimulus; the distinction between them is
hierarchical, with the former being upstream of the latter
(Figure).
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Triggers (or Initiators) of Late PC |
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TopAbstractIntroductionClassification of Late PCComponents of the Mechanism...Triggers (or Initiators) of...The Signaling Pathway of...ConclusionsReferences |
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Brief myocardial ischemia and the ensuing reperfusion are associated with major metabolic perturbations that result in the generation of a wide variety of metabolites and ligands. Among these, there is evidence that adenosine, NO, ROS, and perhaps opioid receptor agonists serve as chemical signals that trigger the development of the late phase of ischemic PC (Figure
).
These substances warn the myocardium that a danger is imminent,
essentially acting as a cellular "alarm system" to which the heart
responds by switching to a defensive phenotype.
Adenosine
The concept that adenosine released during the PC
stimulus triggers the development of delayed protection was first
proposed by Baxter et al14
and subsequently expanded by the same
group21 23 and
others.24 28
Unlike NO, however, which is necessary for the development of
ischemia-induced delayed protection against both myocardial
stunning29 and myocardial
infarction30 and is also
sufficient to trigger both of these forms of
adaptation,13 activation of
adenosine receptors is neither necessary nor sufficient to trigger late
PC against
stunning.18 24 27
The differential role of adenosine receptors in the genesis of late PC
against infarction vis-à-vis late PC against stunning is but one of
several pieces of evidence suggesting the existence of important
differences in the mechanisms underlying these 2 phenomena (see
above).
The identity of the adenosine receptor subtype(s) responsible for triggering late PC is under investigation. Because 2-chloro-N6-cyclopentyladenosine (CCPA) is highly selective for A1 receptors and because CCPA-induced late PC is blocked by selective A1 receptor antagonists,28 it seems likely that this agonist elicits delayed cardioprotection by activating A1 receptors. Recent studies indicate that delayed protection against infarction can also be triggered by selective activation of adenosine A3 receptors.28 Thus, it appears that pharmacological stimulation of either A1 or A3 receptors can elicit late PC against infarction. Whether only one or both of these adenosine receptor subtypes contributes to triggering ischemia-induced late PC is unknown, because 8-p-sulfophenyl theophylline (the only adenosine receptor antagonist shown to block the development of late PC after an ischemic stress)14 is not selective for A1 versus A3 receptors.
Nitric Oxide
The first indication that NO triggers late PC was
provided by a study in which administration of
N
-nitro-Ld-arginine
(L-NA), a nonselective inhibitor of all 3 NO synthase (NOS) isoforms
(neuronal [nNOS], endothelial [eNOS], and inducible
[iNOS]), before the PC ischemic stimulus was found to block the
development of delayed protection against myocardial
stunning,29 demonstrating
that NO generation during the initial PC ischemia is necessary to
trigger this cardioprotective phenomenon. A subsequent study
demonstrated that NO is also necessary to trigger ischemia-induced late
PC against myocardial
infarction.30 Importantly,
exposure to exogenous NO is sufficient to reproduce late PC, since
pretreatment with NO donors in the absence of ischemia induces a
delayed protective effect against both myocardial stunning and
infarction that is indistinguishable from that observed during the late
phase of ischemic
PC.13 31 32 33
Administration of nitroglycerin can elicit late PC both by the
intravenous31 33
and the transdermal33 route;
this salubrious effect is not abrogated by the development of nitrate
tolerance, indicating that different mechanisms underlie the
hemodynamic and PC actions of
nitrates.33 The ability of
NO-releasing agents such as nitrates to faithfully mimic the late phase
of ischemic PC despite nitrate tolerance supports the possibility of
novel clinical applications of these drugs.
Recent studies34 have provided direct evidence of enhanced biosynthesis of NO in myocardium subjected to brief episodes of ischemia/reperfusion. The source of increased NO formation during the PC ischemia is likely to be eNOS, since the development of late PC is blocked by pretreatment with the nonselective NOS inhibitor L-NA, but not with the relatively selective iNOS inhibitors aminoguanidine and S-methylisothiourea.35 Interestingly, the development of late PC is not affected by pretreatment with the guanylate cyclase inhibitor ODQ36 but is completely prevented by pretreatment with the antioxidant mercaptopropionyl glycine (MPG).13 37 NO is known to react rapidly with ·O2- to form the peroxynitrite anion (ONOO-), which then protonates and decomposes to generate the hydroxyl radical (·OH) or some other potent oxidant with similar reactivity.38 39 Because MPG scavenges both ONOO- and ·OH,39 40 the ability of MPG to block late PC,13 37 coupled with the failure of ODQ to do so,36 suggests that NO triggers this response via formation of ONOO- and/or secondary ROS, rather than via cGMP-dependent pathways.
Reactive Oxygen Species
The concept that the generation of ROS during the PC
ischemia is essential to trigger delayed protection was first proposed
by Sun et al.12 These
investigators demonstrated in conscious pigs that the administration of
a combination of antioxidants (superoxide dismutase [SOD] plus
catalase plus MPG) during the initial ischemic challenge prevented the
development of late PC against stunning. Similar findings were obtained
in rabbits with MPG alone.37
MPG has also been found to prevent ischemia-induced late PC against
infarction,41
arrhythmias,41 and coronary
endothelial injury19 as well
as heat stress–induced42
and exercise-induced7 late PC
against infarction, thus implicating ROS as initiators of these forms
of delayed protection as well. Conversely, intracoronary infusion of an
ROS-generating solution in rabbits elicits a late-PC
response.43 Taken together,
these
results12 19 37 41 42
suggest that sublethal oxidative stress plays a useful role by
triggering delayed cardioprotection. Further studies will be necessary
to determine the source(s) and the identity of the ROS responsible for
initiating late PC and whether NO and ROS are parts of the same
mechanism (ie, whether ROS are derived from the reaction of NO with
·O2-,
as discussed above) or act in parallel as 2 independent
triggers.
Opioids
Recent data in
rats17 and
mice44 indicate that
pharmacological activation of 
1-opioid
receptors induces a delayed infarct-sparing effect 24 to 48 hours
later. Whether 1-opioid receptors are also
involved in triggering the late phase of ischemia-induced PC is
currently unknown.
Mediators (or Effectors) of Late PC
Ischemic PC causes an increase in the rate of
myocardial protein synthesis; if this increase is blocked with
cycloheximide, the development of delayed protection is also
blocked.45 Thus, unlike
early PC, late PC requires increased synthesis of new proteins, not
simply activation of preexisting
proteins.45 The time course
of the enhanced tolerance to ischemia, which requires 12 to 24 hours to
develop and lasts for 3 to 4
days,46 47 is
also consistent with the synthesis and degradation of cardioprotective
proteins. Several proteins have been proposed as possible mediators (or
effectors) of the protection afforded by late PC, including NOS,
cyclooxygenase-2 (COX-2), aldose reductase, antioxidant enzymes
(particularly Mn SOD), and heat stress proteins (HSPs). In
addition, considerable evidence implicates KATP
channels as mediators of this defensive
phenotype.
Nitric Oxide Synthase
The first demonstration that the cardioprotective
effects of the late phase of ischemic PC are mediated by NOS was
provided by 2 studies in conscious rabbits, in which the delayed
protection against both myocardial
stunning35 and myocardial
infarction48 was found to be
completely abrogated when preconditioned animals were given L-NA 24
hours after ischemic PC, just before the second ischemic challenge. The
same effects were observed with the relatively selective iNOS
inhibitors aminoguanidine and
S-methylisothiourea,
implicating iNOS as the specific NOS isoform involved in mediating the
protective effects of late
PC.35 48 These
results were subsequently confirmed by
others.49 Because of the
limited selectivity and possible nonspecific effects of iNOS
inhibitors, however, conclusive identification of the NOS isoform
responsible for enhancing tolerance to ischemia during late PC cannot
be attained pharmacologically. Using an in vivo murine model of
myocardial infarction, Guo et
al50 were the first to
demonstrate that the late phase of ischemic PC is associated with
upregulation of myocardial iNOS (whereas eNOS remains unchanged) and
that targeted disruption of the
iNOS gene completely abrogates
the delayed infarct-sparing effect, providing unequivocal molecular
genetic evidence for an obligatory role of iNOS in the cardioprotection
afforded by the late phase of ischemic PC. Immunohistochemical and in
situ hybridization studies have identified cardiac myocytes as the
specific cell type that expresses iNOS during late
PC.51
Thus, NO appears to play a dual role in the pathophysiology of the late phase of ischemic PC, acting initially as the trigger13 29 30 31 32 33 and subsequently as the mediator35 48 49 50 51 of this adaptive response ("NO hypothesis of late PC").52 In support of a dual role of NO are also direct measurements of NOS activity, which have shown a biphasic regulation of NOS by ischemic PC, with an increase in calcium-dependent NOS (cNOS [eNOS and/or nNOS]) activity immediately after the PC ischemia followed by an increase in calcium-independent NOS (iNOS) activity (with no change in cNOS activity) 24 hours later.34 The finding that both ischemic PC and nitroglycerin induce a rapid increase in steady-state levels of iNOS mRNA, which is abolished by administration of L-NA before the PC ischemia53 (NO-dependent iNOS induction), is also congruent with this concept. Taken together, the studies reviewed above13 29 30 31 32 33 34 35 48 49 50 51 52 53 support a complex paradigm in which 2 different NOS isoforms are sequentially involved in the pathophysiological cascade of late PC, with eNOS generating the NO that initiates the development of the PC response on day 1 and iNOS then generating the NO that protects against recurrent ischemia on day 2 (reviewed in Reference 5252 ).
The quantitative aspects of the upregulation of iNOS after
ischemic PC are noteworthy. In the Guo et
al50 study, the increase in
cardiac iNOS protein expression was mild, 
18-fold less than that
observed after a lethal dose of lipopolysaccharide. This supports the
hypothesis50 that induction
of iNOS after ischemic PC is protective because it is relatively
modest, in contrast to other situations (such as inflammation or septic
shock) in which iNOS induction is massive and promotes tissue injury.
The precise mechanism(s) whereby iNOS-derived NO protects against
ischemia remains to be elucidated but appears to involve the activation
of guanylate cyclase, given that both the alleviation of stunning and
the reduction in infarct size are abrogated by
ODQ.54
Besides ischemia-induced PC, there is now evidence that
other forms of late PC are also iNOS dependent. Guo et al found that
the delayed infarct-sparing effects elicited by
S-nitroso-N-acetylpenicillamine
and nitroglycerin,55 by the
selective 1-opioid receptor agonist
TAN-670,44 and by exercise
(Y. Guo and R. Bolli, unpublished observations, 2000) were
completely abrogated in
iNOS-/-
mice, demonstrating that iNOS serves as an obligatory mediator of NO
donor–induced, 1-opioid receptor-induced,
and exercise-induced late PC against infarction. Similarly, iNOS
activity has been found to be necessary for the delayed infarct size
limitation observed after pretreatment with endotoxin derivatives (MLA
and
RC-552)16 56 57
and diazoxide.58 Recent
reports on the role of iNOS in CCPA-induced late PC have arrived at
conflicting
conclusions.44 59 60
Cyclooxygenase-2
An obligatory role of COX-2 in late PC was first shown
by Shinmura et al.61 Using
conscious rabbits, this study found that COX-2 protein expression was
upregulated 24 hours after ischemic PC, concomitant with an increase in
the myocardial levels of prostaglandin (PG) E2,
6-keto-PGF1 (the stable metabolite of
PGI2), and (to a lesser extent)
PGF2. Administration of 2 unrelated
COX-2–selective inhibitors (NS-398 and celecoxib) 24 hours after
ischemic PC abolished the increase in prostanoids and, at the same
time, completely blocked the cardioprotective effects of late PC,
demonstrating that COX-2 activity is necessary for this phenomenon to
occur.61 Similar results
were subsequently obtained in
mice.62 These observations
identify COX-2 as a cardioprotective protein and strongly point to
PGE2 and/or PGI2 as the
likely effectors of COX-2–dependent protection. Induction of COX-2 is
generally though to be
detrimental.63 The finding
that COX-2 mediates the antistunning and antiinfarct effects of late PC
impels a reassessment of current views regarding this enzyme and
supports a more complex paradigm in which COX-2 can play either a
beneficial or a deleterious role depending on various factors (eg, the
intensity of its induction, the pathophysiological setting, and the
ability of specific cell types to metabolize
PGH2 produced by COX-2 into cytoprotective
prostanoids).61
The recognition that iNOS and COX-2 are co-induced and serve as co-mediators of late PC logically leads to the question of whether there is an interaction between these 2 proteins or they act as independent effectors of cytoprotection. Previous studies have suggested that NO can directly activate COX-2.64 In keeping with these data, we have recently observed in unpublished studies that inhibition of iNOS blocks the increased COX-2 activity associated with late PC, whereas inhibition of COX-2 has no effect on iNOS activity, suggesting that COX-2 is downstream of iNOS in the preconditioned heart.
Aldose Reductase
Oxidative stress, osmotic stress, cytokines, and NO are
known to upregulate the expression of aldose reductase, an enzyme that
catalyzes not only the metabolism of glucose to sorbitol but also the
detoxification of ROS-derived lipid
aldehydes.65 Shinmura et
al66 have recently found
that the protein expression of aldose reductase is upregulated 24 hours
after ischemic PC in conscious rabbits and that inhibition of this
enzyme abrogates the infarct-sparing effects observed in untreated
animals. Thus, in addition to iNOS and COX-2, aldose reductase is a
third necessary mediator of the cardioprotective actions of the late
phase of ischemic PC. The mechanism whereby aldose reductase enhances
resistance to ischemia/reperfusion remains to be determined but could
involve the removal of toxic byproducts of lipid peroxidation such as
4-hydroxy-trans-nonenal.65
Antioxidant Enzymes (Mn SOD)
Studies in dogs have shown that ischemic PC induces, 24
hours later, an increase in the protein expression and activity of Mn
SOD (while other antioxidant enzymes are
unchanged)67 and that the
time course of Mn SOD induction parallels that of protection against
lethal ischemia/reperfusion
injury.2 A similar
association between the time course of Mn SOD induction and that of
delayed cardioprotection has been observed after heat
stress,42
exercise,7 and administration
of CCPA,68 although in one
study69 heat stress did not
augment Mn SOD activity. The increase in Mn SOD activity after heat
stress and exercise appears to be caused by the production of ROS,
TNF-, and
interleukin-1ß.7 42 70
Importantly, in vivo administration of antisense oligodeoxynucleotides
to Mn SOD has been reported to block heat
stress–induced,70
exercise-induced,7 and
CCPA-induced71 late PC,
indicating that Mn SOD upregulation is essential for these 3 forms of
delayed cardioprotection. No such data are available to determine
whether Mn SOD is necessary for ischemia-induced late PC in vivo
(although evidence supporting this concept has been obtained in
isolated neonatal
myocytes).72 An increase in
the activity of various antioxidant enzymes (Mn SOD, Cu-Zn SOD,
catalase, and/or glutathione peroxidase) has also been reported
24 to 72 hours after pharmacological PC with
interleukin-173 and
endotoxin,74 concomitant
with increased myocardial resistance to ischemia/superfusion injury,
but a cause-and-effect relationship remains to be established. Not all
studies, however, have found upregulation of antioxidant defenses
during late PC. In conscious
pigs75 and
rabbits76 subjected to
ischemic PC, no increase in Mn SOD, Cu-Zn SOD, catalase, glutathione
peroxidase, or glutathione reductase activity could be detected 24
hours after the PC stimulus, when the delayed cardioprotection was
fully manifest. Thus, the role of antioxidant proteins in
ischemia-induced late PC is currently unknown.
Heat Stress Proteins
Although studies in transgenic mice overexpressing
HSP70 have shown that this protein confers protection against
ischemia/reperfusion
injury,77 78 79
it remains controversial whether ischemic or pharmacological PC
upregulates HSPs in vivo. For example, whereas earlier investigations
reported an increase in myocardial HSP70 content 24 hours after
ischemic PC,3 80
subsequent studies found no HSP70 induction in rabbits preconditioned
with ischemia,81
CCPA,21 82 83
or MLA.84 85
Furthermore, several studies in rats subjected to whole-body
hyperthermia86 87 88
or to ischemic PC89 have
shown that the changes in myocardial HSP70 and HSP27 content do not
correlate with protection against infarction. In addition, induction of
HSP70 by heat stress fails to confer delayed cardioprotection in
mice.69 Recently, another
member of the HSP family, HSP27, has been suggested to participate in
late PC. Studies in rabbits have shown that CCPA-induced late PC is
associated with a redistribution of HSP27 from the membranous to the
cytosolic fraction of the
homogenate90 and with
increased phosphorylation of this protein, which is abolished by
pretreatment with protein kinase C (PKC) or tyrosine kinase
inhibitors.91 Since HSP27 is
a substrate for the p38 mitogen-activated protein kinase (MAPK)
pathway, which is activated 24 hours after
CCPA,91 the hypothesis has
been proposed that posttranslational modulation of HSP27 may play an
important role in mediating the delayed cardioprotection afforded by
CCPA.91
The evidence reviewed above suggests that induction of HSPs is unlikely to account for the cardioprotection afforded by late PC, because the expression of these proteins does not correlate with the presence of the late infarct-sparing effects induced by 4 different stimuli (ischemia, heat stress, adenosine A1 agonists, and MLA). It appears that increased expression of HSPs might be just a marker of the response of myocytes to stress.
KATP Channels
Pharmacological studies have provided evidence that
opening of KATP channels is necessary for the
infarct-sparing effects of late PC induced by
MLA,20 heat
stress,22
ischemia,25 26
adenosine
A128 83 92
and
A328
receptor agonists, and 1-opioid receptor
agonists.17 The diversity of
the PC stimuli that converge on KATP channels
suggests that the activity of these channels may be a common distal
mechanism of delayed protection against cell death. In contrast to late
PC against infarction, however, ischemia-induced late PC against
stunning does not appear to require KATP channel
activity.26 The differential
role of KATP channels in late PC against
stunning versus late PC against infarction provides further evidence
that different mechanisms underlie these 2 forms of cardioprotection,
as mentioned above.
Major issues that remain to be elucidated are the identity of the KATP channels involved in late PC (ie, sarcolemmal versus mitochondrial) and the mechanism whereby their opening confers protection. Given the limitations of the available pharmacological tools, it seems likely that definitive assessment of the role of mitochondrial versus sarcolemmal KATP channels will require molecular approaches (eg, gene targeting or transgenesis).
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The Signaling Pathway of Late PC |
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TopAbstractIntroductionClassification of Late PCComponents of the Mechanism...Triggers (or Initiators) of...The Signaling Pathway of...ConclusionsReferences |
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The stimuli listed in Table 1
trigger late PC by activating a complex cascade of
signaling events that ultimately results in increased transcription of
cardioprotective genes. Among the various families of cellular kinases,
there is now convincing evidence that PKC and Src protein tyrosine
kinases (PTKs) play an essential role in the development of late
PC.
Protein Kinase C
The notion that PKC is essential for the genesis of
late PC was first proposed by Baxter et
al,93 who found that the
delayed infarct-sparing effects of ischemic PC in rabbits were
abrogated by pretreatment with the PKC inhibitor chelerythrine.
Conversely, administration of the PKC activator
dioctanoyl-sn-glycerol induced
cardioprotection 24 hours
later.94 Subsequent studies
have also implicated PKC in the development of
CCPA-induced95 and heat
stress–induced86 88 96
late PC against infarction. Direct evidence that PC stimuli activate
PKC in vivo, however, was lacking. Furthermore, no information was
available as to which PKC isoform is involved. These issues were
addressed in a series of studies in conscious
rabbits97 98 99 100
in which it was found that ischemic PC causes selective translocation
(and activation100 ) of
PKC
and PKC
(2 members of the subfamily of novel PKC isoforms)
but does not affect the other 8 isoforms expressed in the rabbit heart
(PKC isoforms , ß, 
, , 
, 
, 
, and µ) and does not
significantly change total PKC
activity.97 Inhibition of
PKC translocation (and
activation100 ) by
chelerythrine blocked the development of late PC against myocardial
stunning, whereas inhibition of PKC translocation did not,
indicating that the translocation of PKC (but not that of PKC) is
necessary for late PC to
occur.98 Thus, activation of
PKC after ischemic PC is isoform selective and appears to be the
specific PKC isotype responsible for the development of delayed
protection. The ischemic PC–induced activation of PKC is caused by
the generation of NO during the initial ischemic stress, because it is
blocked by pretreatment with
L-NA.99 Interestingly,
administration of NO donors in the absence of ischemia induces a
selective activation of PKC quantitatively similar to that induced
by ischemic PC99 ; this event
is essential for NO donor–induced late PC, since coadministration of
chelerythrine blocks both the activation of PKC and the delayed
protection elicited by the NO
donors.99
Thus, the recruitment of the isoform of PKC appears to
be a critical signaling event in the development of both
ischemia-induced and NO donor–induced late PC in rabbits. The recent
finding that transgenic expression of constitutively active PKC
recapitulates both the signaling events and the cardioprotective
effects of late PC supports a role of PKC in mice as
well.101 The precise
mechanism whereby NO activates PKC remains to be elucidated. Because
MPG blocks NO donor–induced late
PC,13 it seems reasonable to
postulate that NO-derived reactive species
(ONOO- and/or ROS) may activate PKC
either by direct oxidative modification or via activation of
phospholipases.99
Protein Tyrosine Kinases
Since >1000 different PTKs have been identified so
far, assessing the contribution of this class of enzymes to late PC
represents a gargantuan task. A role of PTKs in the genesis of
ischemia-induced late PC was proposed on the basis of studies using
genistein,102 which,
however, is a broad inhibitor of most known PTKs and has modest
selectivity for these kinases versus PKC and other kinases. Recent
studies in conscious
rabbits100 103
have focused on 2 major families of PTKs, the Src PTKs and the
epidermal growth factor (EGF) receptor PTKs. It was found that ischemic
PC selectively activates 2 members of the Src family of PTKs (Src and
Lck) (among the 7 members expressed in the rabbit heart) and that this
activation is blocked by chelerythrine, suggesting that these kinases
are distal to PKC.100
Inhibition of Src and Lck activation with lavendustin A (LD-A)
completely abrogates the development of late PC against myocardial
stunning,103 indicating
that Src and/or Lck signaling plays a causative role in this
phenomenon. In contrast, EGF receptor PTKs are not activated by
ischemic PC.100 Thus, Src
and/or Lck (but not EGF receptor PTKs) appear to be essential
components of the signaling pathway responsible for the development of
ischemia-induced late PC and to be downstream targets of PKC
phosphorylation in rabbits. Subsequent studies in mice have
corroborated these concepts by demonstrating that Lck is a direct
substrate of PKC104 and
that targeted disruption of the Lck gene abolishes
ischemia-induced late
PC.105 LD-A has also been
found to block CCPA-induced late
PC,95 implicating tyrosine
kinases in the genesis of this form of adaptation as well. In contrast,
genistein failed to block heat stress–induced late
PC.96
Mitogen-Activated Protein
Kinases
Another potential downstream target of PKC-dependent
signaling during the development of late PC is the MAPK superfamily,
which includes 3 major subfamilies: the p44/p42 MAPKs (or extracellular
signal–regulated kinases [ERKs]), the p38 MAPKs, and the p46/p54
MAPKs (or c-jun N-terminal kinases [JNKs]). Several studies in
isolated hearts have documented that brief myocardial
ischemia/reperfusion is associated with activation of p44/p42 MAPKs,
p38 MAPKs, and
JNKs,106 107
but it is unknown whether the ischemic protocols used in those
investigations elicit late PC. Recent studies in conscious rabbits have
demonstrated that an ischemic PC protocol known to induce delayed
cardioprotection activates all of the 3 MAPK subfamilies, although the
activation of p38 MAPK is
short-lived.108 109
The activation of p44/p42 MAPKs and JNKs is abolished by chelerythrine,
indicating that it is downstream of, and dependent on, activation of
PKC.108 109
Interestingly, selective overexpression of PKC in adult rabbit
myocytes induces activation of p44/p42 MAPKs and protects against
simulated ischemia, an effect that can be abolished by p44/p42 MAPK
inhibitors.108 The critical
unresolved issue now is whether the recruitment of MAPKs contributes to
the development of late PC or is merely an epiphenomenon. Elucidation
of this issue will require studies in in vivo models of late PC in
which the activity of MAPKs is inhibited either with genetic approaches
(eg, gene targeting or transgenesis of dominant-negative mutants) or
with pharmacological agents more specific than those (eg, SB203580)
currently available.
Role of Kinases in Mediating
Protection
In addition to their role in initiating the development
of late PC shortly after the stimulus (day 1), there is mounting
evidence that cellular kinases are also necessary for the protection to
become manifest 24 hours later (day 2)
(Figure).
This concept is supported by the recent finding that administration of
the PTK inhibitor LD-A before the second ischemic challenge (on day 2)
completely abrogates the protective effects of late PC against
myocardial stunning and the concomitant increase in iNOS
activity.103 It appears,
therefore, that PTKs play a bifunctional role in ischemia-induced late
PC, contributing not only to its development shortly after the initial
ischemic stress but also to the occurrence of protection 24 hours
later. The mechanism whereby PTKs participate in the protection on day
2 remains to be established. Because inhibition of PTKs with LD-A on
day 2 abolishes the increase in iNOS activity, it has been suggested
that posttranslational modulation of iNOS proteins via tyrosine
phosphorylation is necessary to activate this enzyme and to confer
tolerance to ischemia/reperfusion
injury.103 In addition, the
recent finding that p38 MAPK activity is markedly increased 24 hours
after administration of CCPA (concomitant with increased
phosphorylation of HSP27) raises the possibility that this subfamily of
MAPKs may also be involved in mediating the protective effects of late
PC.91
Transcription Factors
The recruitment by the PC stimulus of PKC, Src PTKs,
and almost certainly other as-yet-unidentified kinases leads to the
activation of transcription factors that govern the expression of the
cardioprotective genes responsible for late PC. The first
transcription-regulatory element to be identified as an integral
component of the late PC response was nuclear factor-B
(NF-B),110 which is
known to be a major modulator of iNOS, COX-2, and aldose reductase gene
expression. Using conscious rabbits, Xuan et
al110 demonstrated that
ischemic PC induces rapid activation of NF-B and that this event can
be mimicked by infusing NO donors in the absence of ischemia.
Inhibition of NF-B with diethyldithiocarbamate completely abrogated
the cardioprotective effects observed 24 hours later, indicating that
NF-B plays a critical role in the genesis of late
PC.110 The ischemic
PC-induced activation of NF-B was blocked by pretreatment with L-NA,
MPG, chelerythrine, and LD-A (all given at doses previously shown to
block late PC), indicating that the cellular mechanism whereby ischemic
PC activates NF-B involves the formation of NO and ROS and the
subsequent activation of PKC- and PTK-dependent signaling
events.110 Thus, NF-B
appears to be a common downstream pathway though which multiple signals
elicited by ischemic stress (NO, ROS, PKC, and PTKs) act to induce gene
expression in the heart.
Subsequent studies have shown that ischemic PC induces both
serine and tyrosine phosphorylation of IB (the inhibitor of
NF-B) concomitant with PKC-dependent activation of IKK and IKKß
(the serine-threonine kinases that phosphorylate
IB),111 suggesting
that a dual mechanism accounts for the activation of NF-B during
ischemic PC, one via PKC- and IKK-dependent serine phosphorylation of
IB and the other via IKK-independent tyrosine phosphorylation of
IB. The Lck kinase also plays an essential role in the activation
of NF-B induced by ischemia, as this event is absent in
Lck-/-
mice.105 A molecular link
between PKC (the isoform implicated in the genesis of late
PC)97 98 99 100
and NF-B is further supported by studies in adult cardiac myocytes,
in which selective overexpression of PKC has been found to induce
activation of NF-B,112
activation of IKK and
IKKß,113 and serine and
tyrosine phosphorylation of
IB.113 Interestingly,
PKC-induced recruitment of NF-B in cardiomyocytes is abolished by
inhibition of either p44/p42 MAPKs or
JNKs.112
Recruitment of NF-B has also been reported in rat hearts
subjected to short-term protocols of ischemia/reperfusion in
vivo114 and in
vitro,115 but it is not
clear whether these protocols elicit a late PC response in the models
used. In addition, activating protein 1 (AP-1) has been found to be
activated by brief myocardial ischemia in
rats114 and by
overexpression of PKC in
cardiomyocytes.112 Whether
this transcription factor plays a functional role in the development of
the late PC response remains unknown. Given the fact that specific
combinations of 2 or more transcription-regulatory proteins are
obligatorily required for iNOS gene expression and given the
multiplicity of enzymes that co-mediate late PC (eg, COX-2, aldose
reductase, and Mn SOD), it seems likely that the upregulation of iNOS,
COX-2, and other co-mediators after a PC stimulus involves simultaneous
activation of multiple stress-responsive transcription factors acting
in an additive or synergistic manner.
Polygenic Nature of Late PC
As detailed above, there is now solid evidence
that, in addition to KATP channel
activity,17 20 22 25 26 28 83 92
at least 3 stress-responsive, inducible proteins (ie,
iNOS,16 34 35 44 48 49 50 51 52 53 55 56 57 58 59
COX-2,61 62 and
aldose reductase66 ) are
required to mediate the protection afforded by the late phase of
ischemic PC, and at least 2 proteins (iNOS and Mn SOD) are required to
mediate exercise-induced late
PC7 (and possibly
adenosine-induced late
PC)44 59 71
(Table 2). Thus, the paradigm of late PC has evolved from
the original (and in retrospect naïve) proposal that this adaptation
is mediated by one protein to the recognition that the shift of the
heart to a defensive phenotype represents a complex response requiring
the coordinated activation of multiple genes. This is not dissimilar
from other conditions in which the heart changes its phenotype (eg,
hypertrophy). As the number of newly identified mediators of late PC
increases, so will the number of triggers, transcription-regulatory
mechanisms (kinases/transcription factors), and posttranscriptional
modulators involved. Unraveling the complexity of this polygenic
phenotypic change will likely be a challenge for years to
come.
|
Late Versus Early PC
It is useful to recapitulate here some of the
fundamental differences between the early and late phases of PC. Both
early and late PC limit infarct size, but the infarct-sparing effects
of early PC are more
robust.1 2 3 116
On the other hand, late PC mitigates myocardial stunning, whereas early
PC does not.4 The duration of
the protection conferred by the 2 phases (2 to 3
hours116 versus 72 to 96
hours21 46 47
is vastly different, supporting the concept that the late phase may
ultimately have greater clinical usefulness. The duration of the early
phase cannot be extended by continuous infusion of pharmacological
triggers (ie, CCPA)117 nor
by repeated brief ischemic
episodes,118 presumably
because of desensitization of adenosine receptors. This problem should
not apply to late PC, in which stimuli need to be applied only at 48-
to 72-hour intervals to maintain the defensive phenotype. Indeed,
Yellon’s group has demonstrated that the infarct-sparing effects
induced by a single dose of CCPA persist for 72
hours21 and that repeated
administration of CCPA at 48-hour intervals results in the maintenance
of continuous protection against infarction for at least 10 days with
no evidence of downregulation of A1 receptor
function.23 These results
provide proof of concept that late PC can be exploited
pharmacologically to maintain the heart in a chronically preconditioned
state without development of
tolerance.
|
Conclusions |
|---|
|
TopAbstractIntroductionClassification of Late PCComponents of the Mechanism...Triggers (or Initiators) of...The Signaling Pathway of...ConclusionsReferences |
|---|
The heart reacts to a sublethal ischemic stress by mobilizing a complex sequence of cellular events that results in a shift from a naïve (nonpreconditioned) to a defensive (preconditioned) phenotype. Although the exact cellular and molecular mechanisms underlying the phenomenon of late PC remain to be deciphered, remarkable progress has been made in the last few years in our understanding of this powerful cardioprotective adaptation. A schematic representation of the mechanism of late PC is presented in the Figure
.
It is now clear that this is a polygenic process that requires the
synthesis of multiple proteins. Specifically, chemical signals released
by the ischemic stress (such as NO, ROS, and adenosine) are transduced
by a cascade of signaling elements that includes PKC, Src PTKs, and
NF-B to the nucleus where they direct the transcription of iNOS,
COX-2, aldose reductase, and probably other cardioprotective genes
(Figure).
An analogous sequence of events (possibly involving additional genes
such as Mn SOD) can be triggered by a wide
variety of stimuli, including heat stress, exercise, and cytokines.
Thus, late PC appears to be a universal response of the heart to stress
in general. A sustained cardioprotection similar to that afforded by
the late phase of ischemic PC can also be induced pharmacologically
with clinically relevant agents, such as NO donors, adenosine
A1 or A3 receptor
agonists, endotoxin derivatives, and 1-opioid
receptor agonists ("PC mimetics"), suggesting that this endogenous
adaptive response might be exploited for therapeutic purposes. The
extent to which the various forms of nonpharmacological and
pharmacological PC share the same molecular mechanism remains to be
established. Some components of the proposed paradigm (eg, PKC,
PTKs, iNOS, and Mn SOD) appear to be common to several forms of late
PC, but others (eg, adenosine and KATP channels)
appear to differ. Deciphering the mechanism of late PC is important not
only for our understanding of how the heart adapts to stress but also
for its potential clinical implications. The identification of the
cellular basis of this phenomenon should provide a conceptual framework
for developing novel therapeutic strategies aimed at mimicking the
cardioprotective effects of late PC with pharmacological agents (eg,
PC-mimetic drugs) or genetic approaches (eg, transfer of
cardioprotective genes) that can maintain the heart in a sustained or
chronic defensive (preconditioned)
state.
|
Footnotes |
|---|
This manuscript was sent to Stephen F. Vatner, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received April 28, 2000; revision received October 9, 2000; accepted October 9, 2000.
|
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K. Kaiserova, S. Srivastava, J. D. Hoetker, S. O. Awe, X.-L. Tang, J. Cai, and A. Bhatnagar Redox Activation of Aldose Reductase in the Ischemic Heart J. Biol. Chem., June 2, 2006; 281(22): 15110 - 15120. [Abstract] [Full Text] [PDF]
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D. Ramzy, V. Rao, and R. D. Weisel Clinical applicability of preconditioning and postconditioning: The cardiothoracic surgeons's view Cardiovasc Res, May 1, 2006; 70(2): 174 - 180. [Full Text] [PDF]
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D. K. Das and N. Maulik Cardiac genomic response following preconditioning stimulus Cardiovasc Res, May 1, 2006; 70(2): 254 - 263. [Abstract] [Full Text] [PDF]
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 E. B. Manukhina, H. F. Downey, and R. T. Mallet Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Experimental Biology and Medicine, April 1, 2006; 231(4): 343 - 365. [Abstract] [Full Text] [PDF]
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L. Chen, X.-Y. Lu, J. Li, J.-D. Fu, Z.-N. Zhou, and H.-T. Yang Intermittent hypoxia protects cardiomyocytes against ischemia-reperfusion injury-induced alterations in Ca2+ homeostasis and contraction via the sarcoplasmic reticulum and Na+/Ca2+ exchange mechanisms Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1221 - C1229. [Abstract] [Full Text] [PDF]
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Q. Li, Y. Guo, W. Tan, A. B. Stein, B. Dawn, W.-J. Wu, X. Zhu, X. Lu, X. Xu, T. Siddiqui, et al. Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H584 - H589. [Abstract] [Full Text] [PDF]
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L. Mabanta, P. Valane, J. Borne, and M. D. Frame Initiation of remote microvascular preconditioning requires KATP channel activity Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H264 - H271. [Abstract] [Full Text] [PDF]
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 D. A. Brown, A. J. Chicco, K. N. Jew, M. S. Johnson, J. M. Lynch, P. A. Watson, and R. L. Moore Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel in the rat J. Physiol., December 15, 2005; 569(3): 913 - 924. [Abstract] [Full Text] [PDF]
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Y. Guo, A. B. Stein, W.-J. Wu, X. Zhu, W. Tan, Q. Li, and R. Bolli Late preconditioning induced by NO donors, adenosine A1 receptor agonists, and {delta}1-opioid receptor agonists is mediated by iNOS Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2251 - H2257. [Abstract] [Full Text] [PDF]
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X.-L. Tang, H. Takano, Y.-T. Xuan, H. Sato, E. Kodani, B. Dawn, Y. Zhu, G. Shirk, W.-J. Wu, and R. Bolli Hypercholesterolemia Abrogates Late Preconditioning via a Tetrahydrobiopterin-Dependent Mechanism in Conscious Rabbits Circulation, October 4, 2005; 112(14): 2149 - 2156. [Abstract] [Full Text] [PDF]
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Y.-T. Xuan, Y. Guo, Y. Zhu, O.-L. Wang, G. Rokosh, R. O. Messing, and R. Bolli Role of the Protein Kinase C-{epsilon}-Raf-1-MEK-1/2-p44/42 MAPK Signaling Cascade in the Activation of Signal Transducers and Activators of Transcription 1 and 3 and Induction of Cyclooxygenase-2 After Ischemic Preconditioning Circulation, September 27, 2005; 112(13): 1971 - 1978. [Abstract] [Full Text] [PDF]
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S. F. Jones and I. Power Editorial I: Postoperative NSAIDs and COX-2 inhibitors: cardiovascular risks and benefits Br. J. Anaesth., September 1, 2005; 95(3): 281 - 284. [Full Text] [PDF]
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P. C. Beguin, M. Joyeux-Faure, D. Godin-Ribuot, P. Levy, and C. Ribuot Acute intermittent hypoxia improves rat myocardium tolerance to ischemia J Appl Physiol, September 1, 2005; 99(3): 1064 - 1069. [Abstract] [Full Text] [PDF]
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 S. P. Loukogeorgakis, A. T. Panagiotidou, M. W. Broadhead, A. Donald, J. E. Deanfield, and R. J. MacAllister Remote Ischemic Preconditioning Provides Early and Late Protection Against Endothelial Ischemia-Reperfusion Injury in Humans: Role of the Autonomic Nervous System J. Am. Coll. Cardiol., August 2, 2005; 46(3): 450 - 456. [Abstract] [Full Text] [PDF]
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 S. J. Canyon and G. P. Dobson Pretreatment with an adenosine A1 receptor agonist and lidocaine: A possible alternative to myocardial ischemic preconditioning J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 371 - 377. [Abstract] [Full Text] [PDF]
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B. Dawn and R. Bolli HO-1 induction by HIF-1: a new mechanism for delayed cardioprotection? Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H522 - H524. [Full Text] [PDF]
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R. D. Lasley, B. J. Keith, G. Kristo, Y. Yoshimura, and R. M. Mentzer Jr. Delayed adenosine A1 receptor preconditioning in rat myocardium is MAPK dependent but iNOS independent Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H785 - H791. [Abstract] [Full Text] [PDF]
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P. La Padula and L. E. Costa Effect of sustained hypobaric hypoxia during maturation and aging on rat myocardium. I. Mechanical activity J Appl Physiol, June 1, 2005; 98(6): 2363 - 2369. [Abstract] [Full Text] [PDF]
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 J. S. Berg, B. O. Christensen, S. Aagaard, T. B.N. Christensen, D. A. Steinbruchel, and J. M. Hasenkam Ischaemic preconditioning causes increased myocardial vascular resistance but no myocardial contractility changes in pigs after OPCAB Interactive CardioVascular and Thoracic Surgery, June 1, 2005; 4(3): 207 - 211. [Abstract] [Full Text] [PDF]
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Y. Harder, C. Contaldo, J. Klenk, A. Banic, S. M. Jakob, and D. Erni Preconditioning with Monophosphoryl Lipid A Improves Survival of Critically Ischemic Tissue Anesth. Analg., June 1, 2005; 100(6): 1786 - 1792. [Abstract] [Full Text] [PDF]
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Y. Xie, Y. Zhu, W.-Z. Zhu, L. Chen, Z.-N. Zhou, W.-J. Yuan, and H.-T. Yang Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2594 - H2602. [Abstract] [Full Text] [PDF]
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H. Jneid, M. Chandra, M. Alshaher, C. A. Hornung, X.-L. Tang, M. Leesar, and R. Bolli Delayed Preconditioning-Mimetic Actions of Nitroglycerin in Patients Undergoing Exercise Tolerance Tests Circulation, May 24, 2005; 111(20): 2565 - 2571. [Abstract] [Full Text] [PDF]
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D. A Brown, J. M Lynch, C. J Armstrong, N. M Caruso, L. B Ehlers, M. S Johnson, and R. L Moore Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat J. Physiol., April 15, 2005; 564(2): 619 - 630. [Abstract] [Full Text] [PDF]
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M. Ii, H. Nishimura, A. Iwakura, A. Wecker, E. Eaton, T. Asahara, and D. W. Losordo Endothelial Progenitor Cells Are Rapidly Recruited to Myocardium and Mediate Protective Effect of Ischemic Preconditioning via "Imported" Nitric Oxide Synthase Activity Circulation, March 8, 2005; 111(9): 1114 - 1120. [Abstract] [Full Text] [PDF]
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 K. V. Ramana, B. Friedrich, R. Tammali, M. B. West, A. Bhatnagar, and S. K. Srivastava Requirement of Aldose Reductase for the Hyperglycemic Activation of Protein Kinase C and Formation of Diacylglycerol in Vascular Smooth Muscle Cells Diabetes, March 1, 2005; 54(3): 818 - 829. [Abstract] [Full Text] [PDF]
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G. Heusch, R. Schulz, and S. H. Rahimtoola Myocardial hibernation: a delicate balance Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H984 - H999. [Abstract] [Full Text] [PDF]
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T. Date, S. Mochizuki, A. J. Belanger, M. Yamakawa, Z. Luo, K. A. Vincent, S. H. Cheng, R. J. Gregory, and C. Jiang Expression of constitutively stable hybrid hypoxia-inducible factor-1{alpha} protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury Am J Physiol Cell Physiol, February 1, 2005; 288(2): C314 - C320. [Abstract] [Full Text] [PDF]
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A. S. Leon, B. A. Franklin, F. Costa, G. J. Balady, K. A. Berra, K. J. Stewart, P. D. Thompson, M. A. Williams, and M. S. Lauer Cardiac Rehabilitation and Secondary Prevention of Coronary Heart Disease: An American Heart Association Scientific Statement From the Council on Clinical Cardiology (Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity), in Collaboration With the American Association of Cardiovascular and Pulmonary Rehabilitation Circulation, January 25, 2005; 111(3): 369 - 376. [Abstract] [Full Text] [PDF]
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H. Yamasowa, S. Shimizu, T. Inoue, M. Takaoka, and Y. Matsumura Endothelial Nitric Oxide Contributes to the Renal Protective Effects of Ischemic Preconditioning J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 153 - 159. [Abstract] [Full Text] [PDF]
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Y. Shi, W. C. Hutchins, J. Su, D. Siker, N. Hogg, K. A. Pritchard Jr., A. Keszler, J. S. Tweddell, and J. E. Baker Delayed cardioprotection with isoflurane: role of reactive oxygen and nitrogen Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H175 - H184. [Abstract] [Full Text] [PDF]
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L. Xi, M. Taher, C. Yin, F. Salloum, and R. C. Kukreja Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1{alpha} and AP-1 and iNOS signaling Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2369 - H2375. [Abstract] [Full Text] [PDF]
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G. Kristo, Y. Yoshimura, B. J. Keith, R. M. Stevens, S. A. Jahania, R. M. Mentzer Jr., and R. D. Lasley Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2746 - H2753. [Abstract] [Full Text] [PDF]
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X. Wang, C. Yin, L. Xi, and R. C. Kukreja Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2070 - H2077. [Abstract] [Full Text] [PDF]
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 A. B. Stein, X.-L. Tang, Y. Guo, Y.-T. Xuan, B. Dawn, and R. Bolli Delayed Adaptation of the Heart to Stress: Late Preconditioning Stroke, November 1, 2004; 35(11_suppl_1): 2676 - 2679. [Abstract] [Full Text] [PDF]
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D. B. Buxton Cytokines and Late Preconditioning Cardiovasc Res, October 1, 2004; 64(1): 6 - 8. [Full Text] [PDF]
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B. Dawn, Y.-T. Xuan, Y. Guo, A. Rezazadeh, A. B. Stein, G. Hunt, W.-J. Wu, W. Tan, and R. Bolli IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2 Cardiovasc Res, October 1, 2004; 64(1): 61 - 71. [Abstract] [Full Text] [PDF]
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A. Bhatnagar Beating Ischemia: A New Feat of EETs? Circ. Res., September 3, 2004; 95(5): 443 - 445. [Full Text] [PDF]
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E. O. McFalls, M. Hou, R. J. Bache, A. Best, D. Marx, J. Sikora, and H. B. Ward Activation of p38 MAPK and increased glucose transport in chronic hibernating swine myocardium Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1328 - H1334. [Abstract] [Full Text] [PDF]
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M. A. G. Hartlage, E. Berendes, H. Van Aken, M. Fobker, M. Theisen, and T. P. Weber Xenon Improves Recovery from Myocardial Stunning in Chronically Instrumented Dogs Anesth. Analg., September 1, 2004; 99(3): 655 - 664. [Abstract] [Full Text] [PDF]
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C. Depre, S.-J. Kim, A. S. John, Y. Huang, O. E. Rimoldi, J. R. Pepper, G. D. Dreyfus, V. Gaussin, D. J. Pennell, D. E. Vatner, et al. Program of Cell Survival Underlying Human and Experimental Hibernating Myocardium Circ. Res., August 20, 2004; 95(4): 433 - 440. [Abstract] [Full Text] [PDF]
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C. J. McLeod, A. P. Jeyabalan, J. O. Minners, R. Clevenger, R. F. Hoyt Jr, and M. N. Sack Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery Circulation, August 3, 2004; 110(5): 534 - 539. [Abstract] [Full Text] [PDF]
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M. Mayr, B. Metzler, Y.-L. Chung, E. McGregor, U. Mayr, H. Troy, Y. Hu, M. Leitges, O. Pachinger, J. R. Griffiths, et al. Ischemic preconditioning exaggerates cardiac damage in PKC-{delta} null mice Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H946 - H956. [Abstract] [Full Text] [PDF]
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R. V. Plachinta, M. J. M. de Klaver, J. K. Hayes, and G. F. Rich The Protective Effect of Protein Kinase C and Adenosine Triphosphate-Sensitive Potassium Channel Agonists Against Inflammation in Rat Endothelium and Vascular Smooth Muscle In Vitro and In Vivo Anesth. Analg., August 1, 2004; 99(2): 556 - 561. [Abstract] [Full Text] [PDF]
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R. Bolli, L. Becker, G. Gross, R. Mentzer Jr, D. Balshaw, and D. A. Lathrop Myocardial Protection at a Crossroads: The Need for Translation Into Clinical Therapy Circ. Res., July 23, 2004; 95(2): 125 - 134. [Abstract] [Full Text] [PDF]
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Y. Wang, E. Kodani, J. Wang, S. X. Zhang, H. Takano, X.-L. Tang, and R. Bolli Cardioprotection During the Final Stage of the Late Phase of Ischemic Preconditioning Is Mediated by Neuronal NO Synthase in Concert With Cyclooxygenase-2 Circ. Res., July 9, 2004; 95(1): 84 - 91. [Abstract] [Full Text] [PDF]
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M. Zaugg, M. C. Schaub, and P. Foex Myocardial injury and its prevention in the perioperative setting Br. J. Anaesth., July 1, 2004; 93(1): 21 - 33. [Abstract] [Full Text] [PDF]
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A. Crisafulli, F. Melis, F. Tocco, U. M. Santoboni, C. Lai, G. Angioy, L. Lorrai, G. Pittau, A. Concu, and P. Pagliaro Exercise-induced and nitroglycerin-induced myocardial preconditioning improves hemodynamics in patients with angina Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H235 - H242. [Abstract] [Full Text] [PDF]
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G. G. Neri Serneri, M. Boddi, P. A. Modesti, M. Coppo, I. Cecioni, T. Toscano, M. L. Papa, M. Bandinelli, G. F. Lisi, and M. Chiavarelli Cardiac Angiotensin II Participates in Coronary Microvessel Inflammation of Unstable Angina and Strengthens the Immunomediated Component Circ. Res., June 25, 2004; 94(12): 1630 - 1637. [Abstract] [Full Text] [PDF]
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 M. Galagudza, D. Kurapeev, S. Minasian, G. Valen, and J. Vaage Ischemic postconditioning: brief ischemia during reperfusion converts persistent ventricular fibrillation into regular rhythm Eur. J. Cardiothorac. Surg., June 1, 2004; 25(6): 1006 - 1010. [Abstract] [Full Text] [PDF]
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C.-M. Cao, Q. Xia, J. Tu, M. Chen, S. Wu, and T.-M. Wong Cardioprotection of Interleukin-2 Is Mediated via {kappa}-Opioid Receptors J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 560 - 567. [Abstract] [Full Text] [PDF]
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R. Schulz and G. Heusch Connexin 43 and ischemic preconditioning Cardiovasc Res, May 1, 2004; 62(2): 335 - 344. [Abstract] [Full Text] [PDF]
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X.-L. Tang, Y.-T. Xuan, Y. Zhu, G. Shirk, and R. Bolli Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1273 - H1280. [Abstract] [Full Text] [PDF]
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J. A. Auchampach, X. Jin, J. Moore, T. C. Wan, L. M. Kreckler, Z.-D. Ge, J. Narayanan, E. Whalley, W. Kiesman, B. Ticho, et al. Comparison of Three Different A1 Adenosine Receptor Antagonists on Infarct Size and Multiple Cycle Ischemic Preconditioning in Anesthetized Dogs J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 846 - 856. [Abstract] [Full Text] [PDF]
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R. Schulz, M. Kelm, and G. Heusch Nitric oxide in myocardial ischemia/reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 402 - 413. [Abstract] [Full Text] [PDF]
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