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Experimental Diabetes Research
Volume 2012, Article ID 198048, 9 pages
doi:10.1155/2012/198048
Review A rticle
Diabet ic Inhibition of Preconditioning- and
Postconditioning-Mediated Myocardial Protect ion against
Ischemia/Reperfusion Injury
Xia Yin,
1, 2
Yang Z h e n g ,
1
Xujie Zhai,
3
Xin Zhao,
1
and Lu Cai
1, 2
1
The Cardiovascular Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China
2
KCHRI, The Depart ment of Pediatrics, University of Louisville, Louisville, KY 40202, USA
3
Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
Correspondence should be addressed to Yang Zheng, zhengyang@jlu.edu.cn
Received 6 May 2011; Accepted 31 May 2011
Academic Editor: Yingmei Zhang
Copyright © 2012 Xia Yin et al. This is an op en access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortal-
ity of diabetic patients with acute myocardial infarction was found to be 2–6 folds higher than that of non-diabetic patients with
same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms.
Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3β
pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3β
pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the
general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic
inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and
Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore any
strategy to activate PI3K/Akt and associated GSK-3β pathway to release the diabetic inhibition of both IPC and Ipost-mediated
myocardial protection may provide the protective effect against ischemia/reperfusion injuries.
1. Introduction
Acute myocardial infarction (AMI) is a worldwide problem
that threatens the human’s health both in the developed
and developing countries. AMI is often induced by the
complete thrombotic occlusion of coronary arteries at the
site of a ruptured atherosclerotic plaque. Prompt reperfusion
is a definitive treatment to salvage ischemic myocardium
from inevitable death. Experimental and clinical investi-
gations suggest that although reperfusion can salvage the
ischemic myocardium, it can also induce side effect, called
as ischemia/reperfusion injuries. It is appreciated now that
lethal myocardial injury caused by ischemia/reperfusion
accounts for up to 50% of the final infarct size of a myocardial
infarct [1].
Myocardial ischemia/reperfusion injury is a complex
pathophysiological event, resulting in serious acute and
chronic myocardial damage. It is characterized by a cas-
cade of acutely initiated local inflammatory responses,
metabolic disorder, and cell death, leading to myocardial
ultrastructural changes and remodeling and subsequently
myocardial systolic and diastolic dysfunction [2–4]. Myocar-
dial ischemia/reperfusion injury also induces ventricular
arrhythmias, resulting in circulation collapse and sudden
death [5, 6].
Nu merous studies have demonstr a ted that inflammation
following ischemia/reperfusion injury exacerbates myocar-
dial injury [4, 7]. In addition to inflammation, profound
alterations in myocardial metabolism, such as the disarr ange-
ment of glycolysis and fatty acid oxidation, also significantly
2 Experimental Diabetes Research
impact on the cell integrity and functional recovery of the
myocardium [8]. Evidence from previous studies suggests
that reactive oxygen or nitrogen species (ROS or RNS),
including superoxide radicals, hydrogen peroxide, hydroxyl
radicals, singlet oxygen, nitric oxide, and peroxynitrite
play major contribution to myocardial ischemia/reperfusion
injury [9, 10]. These ROS and/or RNSs, which are formed
within the ischemic myocardial cells and in the first few
moments of reperfusion, are known to be cytotoxic to
surrounding cells. In addition, it is also widely accepted
that apoptotic cell death is involved in the development of
ischemic myocardial damage [11]. Therefore, how to protect
the ischemic myocardium from reperfusion injury is the
key issue for cardiologist and cardiovascular physicians. This
review briefly overviews the status of ischemic precondition-
ing (IPC) and ischemic postconditioning (Ipost) with an
emphasis of the diabetic effects on the myocardial protection
of IPC and Ipost as well as possible mechanisms.
2. Ischemic Preconditioning, Postconditioning,
and Their Myocardial Protective Mechanisms
2.1. Ischemic Preconditioning and Its Myocardial Protection.
Mur ry et al. (1986) first found the potent myocardial pro-
tection by preconditioning the ischemic myocardium when
they gave transient and repeat ischemia and reperfusion
before the occlusion of the coronary artery in dog heart
[12]. They found that multiple brief ischemic episodes
actually protected the myocardium from a subsequent
sustained ischemic insult. They called this prote ctive effect
as IPC (Figure 1). IPC is a well-described adaptive response
by which brief exposure to ischemia/reperfusion before
sustained ischemia markedly enhances the ability of the
myocardium to withstand a subsequent ischemic insult [13].
The protection of IPC is displayed as the reduction of
ischemia/reperfusion-induced infarct size, arrhythmia, and
the improvement of contractile and diastolic function of the
myocardial muscle. Consequently, many studies indicated
that IPC was an endogenous protection for AMI, by induc-
ing phosphatidylinositol 3-kinase (PI3K), protein kinase C
(PKC) and JAK/STAT pathways [12, 14–17]. Among these,
the activation of PI3K/protein kinase B (Akt) pathway was
found to play an important role in protecting myocardial
ischemia/reperfusion injury [15, 16, 18]. The PI3K/Akt
pathway affects cell survival by a variety of substrates,
including apoptotic proteins, endothelial nitric oxide syn-
thase (eNOS), and PKC [19, 20 ]. More recent interest
has focused on glycogen synthase kinase-3β (GSK-3β)as
a distal kinase, phosphorylated (and hence inactivated) by
other kinases, including Akt and p42/p44 MAPK/ERK [21,
22]. GSK-3β is a multifunctional Ser/Thr kinase that plays
important roles in necrosis and apoptosis of cardiomyocytes.
GSK-3 activity has been associated with many cell processes,
including the regulation of multiple transcription factors,
the Wnt pathway, nuclear factor κB, endoplasmic reticulum
stress, embryogenesis, apoptosis and cell survival, cell cycle
progression, cell migration, and so on [23, 24].
Preconditioning Occlusion
Reperfusion
Occlusion
Postconditioning
Reperfusion
Figure 1: The illustration of IPC and Ipost. IPC means that
transient and repeat ischemia and reperfusions were given before
the occlusion of the coronary artery. Ipost means that transient and
repeat ischemia and reperfusions were given after the occlusion and
before the reperfusion of coronary artery.
IPC produces myocardial protection by phosphorylating
and consequently inactivating GSK-3β [21]. Howe ver, since
ischemic event is unpredictable and IPC is also invasive,
myocardial protection by IPC is difficult to be used in clinics.
In this review, we do not introduce the detail status of
IPC myocardial protection and possible mechanisms since
these issues have been extensively discussed in a few recent
excellent reviews [25–28].
2.2. Ischemic Postconditioning and Its Myocardial Protection.
The Ipost came into notice of Zhao et al. (2003) when
they moved the transient and repeat ischemia/reperfusions to
after the occlusion and before the reperfusion, as illustrated
in Figure 1 [2]. Subsequently, a lot of researchers reported
the same protective effects [29, 30]. They found that cycles
of brief reperfusion and ischemia performed immediately
at the onset of reperfusion following a prolonged ischemic
insult markedly limited reperfusion injury. Like IPC, the
Ipost is also a powerful approach to protect the ischemic
myocardium from reperfusion-induced damage [31–33]. In
clinics, with the development of percutaneous coronary
intervention emerged as an exciting innovative treatment
strategy, it makes Ipost possible to intervene AMI. A recent
analysis of data on infarct size and ischemic zone size
indicates that current reperfusion therapy salvages more than
50% of the ischemic myocardium in approximately half of
the patients with AMI [34].
It has been supported by several studies that Ipost
protected the myocardium against the detrimental effects
of lethal myocardial reperfusion injury by limiting oxida-
tive stress, reducing calcium accumulation, maintaining
endothelial function, and reducing inflammation [35–37].
Subsequent studies have identified a number of signaling
pathways which are activated by Ipost, and involve in the
myocardial protection of Ipost. Among these pathways,
reperfusion injury salvage kinase (RISK) pathway was the
first sig naling cascade to be linked to Ipost [21], which
showed that Ipost was capable of recruiting prosurvival
signal cascades including PI3K/Akt, PKC, GSK-3β,eNOS,
and guanylyl-cyclase, as disclosed for the mechanisms of IPC
myocardial protection (see the above discussion).
The discovery of IPC and Ipost, including pharmaco-
logical preconditioning and postconditioning, as the two
major forms of endogenously protective mechanisms in the
Experimental Diabetes Research 3
myocardium have encouraged us to explore new ways to
protect the myocardium from ischemia/reperfusion and have
enriched our knowledge of the molecular basis of injury and
survival during ischemia/reperfusion [13]. In both IPC- and
Ipost-mediated myocardial protections, PI3K/Akt activation
is considered as an initial step that induces phosphory-
lation of downstream kinases to inhibit the several pro-
apoptotic factors and mitochondrial permeability transition
pore (mPTP)’s opening at reperfusion, as illustrated in
Figure 2 [23 , 38–44]. One of the downstream targets of
the RISK pathway is GSK-3β that plays important roles
in necrosis and apoptosis of cardiomyocytes [23]. GSK-3β
links to the regulation of a variety of cellular functions
including glycogen metabolism, gene expression, and cellular
survival. Experimental studies have demonstrated that the
phosphorylation or inactivation of GSK-3β confers myocar-
dial protective effects through its potential mitochondrial
effects that include the inhibition of mPTP’s opening and
the control of mitochondrial a denine nucleotide transport
through the outer mitochondrial membrane [35–37]. The
mPTP is a nonselective large conductance channel in the
mitochondrial inner membrane, which is physiologically
closed. The mPTP remains closed during ischemia but
opens at the onset of reperfusion [45], and modulation
of the mPTP opening at early reperfusion can protect the
myocardium from reperfusion injury [46, 47 ].
Opening of mPTPs is involved in cell death induced by
a variety of causes, including ischemia/reperfusion, alcohol,
endotoxin, and anticancer agents [48]. In addition to
Ca
2+
, ROS and/or RNS-caused accumulation of inorganic
phosphate and depletion of ATP all can open mPTPs [49,
50]. It is also clear that all of these mPTP opening stimuli
are induced in cardiomyocy tes subjected to long-sustained
ischemia/reperfusion. Ipost significantly elevated the thresh-
old of mPTP’s opening in myocardial mitochondria [23].
The inhibition of mPTP’s opening plays a critical end effector
for the myocardial protective effects of Ipost. Juhaszova et
al. [21] first reported that GSK-3β activity is a determinant
of the threshold for mPTP’s opening in cardiomyocytes.
Therefore, GSK-3β plays a critical role in IPC- and Ipost-
mediated myocardial protect ion.
So far, there were two studies that have examined the
role of GSK-3β as an obligatory mediator of Ipost using
transgenic mice and showed different results. Gomez et al.
[35] found that mice containing a mutant form of GSK-
3β (which cannot be phosphorylated and inhibited) were
resistant to the myocardial infarct-limiting effects of Ipost
in situ, suggesting that GSK-3β inactivation is required
for Ipost’s myocardial protection. Contrast to the study of
Gomez et al., Nishino et al. [51]havereportedthatmicewith
amutantformofbothGSK-3β and GSK-3α in which the
Akt phosphorylation sites were changed, thereby rendering
them to resistant to inactivation, were still amenable to the
myocardial infarct-limiting effects of both IPC and Ipost.
This study suggests that GSK-3β and GSK-3α inactivation
are not necessary for myocardial protection in these settings.
Therefore, the exact role of GSK-3β in the setting of Ipost
remains further investigation, par ticularly under different
conditions.
Preconditioning Postconditioning
Growth factors
G-protein-coupled receptor
PDK1
JAK2
PI3K
STAT3
Akt
p-Akt
GSK-3β
DM
mPTP’s
opening
Cell death
p-GSK-3β
Figure 2: Major signaling pathways of IPC- and Ipost-mediated
protection against cardiac cell death. Myocardial protection of
IPC and Ipost were proposed to be mediated by stimulation of
the prosurvival signaling pathway—PI3K/Akt pathway to inhibit
the GSK-3β activation either via PI3K pathway or JAK2/STAT3
pathway. Diabetes (DM) can inhibit the activation of STAT3 or Akt
to consequently activate GSK-3β that in turn induces mitochondrial
cell death that is the critical cellular event for ischemia/reperfusion-
induced myocardial infarction.
3. Diabetic Inhibition of Ischemic
Preconditioning- and Postconditioning-
Mediated Myocardial Protection against
Ischemia/Reperfusion Injury
Epidemiological data show that diabetes is a major risk
for cardiovascular morbidity and mortality [52, 53]. Coro-
nary artery diseases leading to myocardial infarction and
myocardium failure are one of the major chronic complica-
tions of diabetes, accounting for >75% of hospitalizations in
diabetic patients. The mortality rate of diabetic patients after
AMI is 2–6 folds higher than that of nondiabetic patients
[54, 55]. Increased mortality or increased myocardial injury
following AMI in diabetes is thought probably because of the
high prevalence of other risk factors, that is, hypertension,
hyperlipidemia, and advanced coronary artery diseases [56].
The poor prognosis may b e also in part because of an
increase in the myocardial injury in response to ischemia and
reperfusion [57].
It is well known that insulin regulates metabolism in the
myocardium by modulating glucose transport, glycolysis,
glycogen synthesis, lipid metabolism, protein synthesis,
4 Experimental Diabetes Research
growth, contractility, and apoptosis in cardiomyocytes [58,
59]. Myocardial insulin resistance develops in animal models
of both type 1 and type 2 diabetes [59]. These insulin-
stimulated effects have been shown to be reduced in the
myocardium and cardiomyocytes of diabetic rats [60], which
may be the main reason for the increase in myocardial
injury in response to ischemia and reperfusion in diabetic
subjects.
In normal physiological status, insulin can regulate the
metabolism of glucose through PI3K/Akt pathway. Insulin
binds to its receptor and phosphorylates insulin receptor’s
substrates (IRS) such as IRS protein 1–4, Shc, Grb-2 asso-
ciated binder-1, and APS adapter protein. These substrates
have the SH2 structural domain and can provide the orienta-
tion sites for other signaling protein molecules, including the
downstream signaling molecules of PI3K [61, 62]. Activated
PI3K can phosphorylate the PI’s substrates specifically to
produce PIP2 and PIP3. PIP1 and PIP2 can translocate the
PI3K-dependent kinase (PDK1) and Akt from the cytoplasm
to plasma membrane. Under these conditions, Akt can be
phosphorylated at Thr308 and Ser473, and the activated Akt
then phosphorylates GSK-3β. The phosphorylation of GSK-
3β inactivates its ac tivity, which will release its inhibition
of the synthesis of glycogen, as shown in Figure 2.The
activity of GSK-3β is two-fold higher in diabetes than that of
nondiabetes. Hyperglycemia and hyperinsulinemia can both
activate the GSK-3β [43, 44, 63]. The activated GSK-3β can
inhibit the myocardial transduction of insulin signaling and
the utilization of glucose through the phosphorylation of
IRS-1.
We have recently reported for the first time that the
activation of GSK-3β played the pivotal role in diabetes-
induced energy disarrangement a nd consequently patholog-
ical remodeling in the myocardium [63]. This study suggests
that the activation of GSK-3β plays an important role in the
development of diabetic cardiomyopathy.
Diabetes is an independent risk factor for ischemic
myocardium disease; therefore, whether diabetes could
decrease the IPC and/or Ipost protection against ischemia/
reperfusion-induced myocardial damage has been ques-
tioned. Tosaki et al. found that IPC did not afford protection
against ischemic damage in diabetic subjects [76]. Other
studies also showed that STZ-induced diabetes signifi-
cantly aggravated myocardial ischemia/reperfusion injury
and blunted the protective effects of IPC [77, 78]. However,
whether diabetes abrogates IPC- or Ipost-mediated myocar-
dial protection depends on IPC times or the periods of dia-
betes. For instance, Tsang et al. [15] discovered that in nor-
mal Wistar rats, one, two, and three cycles of IPC significantly
reduced infarct size induced by ischemia/reperfusion; how-
ever, in diabetic Goto-Kakizaki (GK) rats, only three cycles
of IPC reduced infarct size induced by ischemia/reperfusion,
compared with GK control hearts. Both one and two cycles
ofIPCfailedtoafford reductive effect on the infarct,
suggesting that the diabetic heart has a high threshed to IPC
stimulus-induced myocardial protection. In addition, Shi-
Ting et al. [79] also showed that mice with diabetes for 4
weeks showed a tolerance to ischemia/reperfusion-induced
damage as compared to normal rats; IPC of these diabetic
mice remained affording partial myocardial protection. In
contrast, mice with diabetes for 8 weeks showed a low
tolerance to ischemia/reperfusion damage as compared to
normal mice, and the IPC-induced myocardial protection
was not evident. These findings suggest that shor t-term dia-
betes makes the myocardium more tolerant, like an adaptive
response, but long-term diabetes makes the myocardium
more susceptible to ischemia/reperfusion-induced damage,
like a decompensated response.
Recently, Przyklenk et al. [80] have assessed the con-
sequences of a major risk factor—diabetes on the infarct-
sparing effect of stuttered reflow using type 1 and type 2 dia-
betic mouse models. They gave the isolated buff
er-perfused
myocardium for 30 min ischemia, and the myocardium
received either standard reperfusion or three to six 10s cycles
of stuttered reflow as Ipost. They found that Ipost-reduced
infarct size via upregulation of extracellular signal-regulated
kinase 1/2 (ERK1/2) in nor moglycemic mice, but diabetic
myocardium was refractory to Ipost-induced cardioprotec-
tion. They also found that in the type-1 diabetic model,
Ipost’s protective effects were reversed by the restoration
of normoglycemia. Therefore, this study provided strong
evidence for a profound, but potentially reversible, defect
induced by diabetes in the myocardial protection of Ipost.
In a study by Drenger et al. [81], however, the protective
effects of Ipost were found to be inhibited in the diabetes rats,
and the diabetic inhibition of Ipost’s myocardial protection
was not relieved by insulin-induced normoglycemia. The
discrepancy between these two studies may be also due to
hyperglycemic times; as the hyperglycemic time increases,
the inhibited protective function of Ipost by diabetes may
become irreversible.
As the myocardial protection of IPC and Ipost is medi-
ated by a number of signaling pathways, the blunted myocar-
dial protection mediated by IPC in diabetes may be related to
the impairment in myocardial protective signaling pathways
such as the PI3K/Akt pathway, as illustrated in Figure 2 [2,
15, 77]. Since signal tr ansducer and activator of transcription
(STAT) 3-mediated signaling pathway has been found to
play an important role in the cardiac protection induced
by IPC [14]andIpost[69]. Downregulation of STAT3
was found to be a causative of abolishment of the cardiac
protection mediated by IPC [17]andIpost[81–83 ]under
several conditions. Therefore, STAT3 downregulation may
be one of the mechanisms for diabetic inhibition of Ipost-
mediated cardiac protection, as discussed by Drenger et al.
[81]. Reportedly erythropoietin (EPO) has an IPC-like effect
to show myocardial protection against ischemia/reperfusion-
induced damage [73, 74]. However, Ghaboura et al. have
shown the attenuation of EPO-mediated myocardial protec-
tion under diabetic condition [43].
4. Diabetic Activation of GSK-3β Plays a Critical
Role in Diminishing IPC- and Ipost-Mediated
Myocardial Protective Function
In the above sections, we mentioned that there are several
signaling pathways that may involve in the myocardial
Experimental Diabetes Research 5
Table 1: Potential candidates that may have protective effect against ischemia reperfusion injury related with Akt/GSK-3β pathway.
Potential candidates Target of signaling pathway Reference
Lithium chloride GSK-3β inhibitor [44]
Indirubin-3 monooxime GSK-3β inhibitor [44]
SB216763 GSK-3β inhibitor [44]
Zinc Inactivation of GSK-3β directly or indirectly [42, 64–67]
Adenosine Activation/translocation of PKC, PI3K, and MAPK [68]
Endogenous opioids JAK-STAT pathway and then inactivation of GSK-3β [69–72]
Erythropoietin Activate Akt and inhibit GSK-3β [43, 73, 74]
Sevoflurane Phosphor ylates Akt and then GSK-3 β [75]
Except for the GSK-3β inhibitors, most of other potential candidates may exert their protective effect against ischemia reperfusion injury through activation
of Akt and then inactivation of GSK-3β.
protection mediated by IPC or Ipost. As shown in Figure 2,
however, inactivation of GSK-3β has been considered as the
pivotal step for both IPC and Ipost’s myocardial protec-
tion. Furthermore, studies have demonstrated that diabetes-
induced activation of GSK-3β and impairment of RISK
play critical roles in diabetes-induced myocardial oxidative
damage and remodeling [43, 63]; other studies also reported
that the activity of GSK-3β is twice in diabetic patients
compared to that of nondiabetic patients [84]. Therefore,
whether diabetic activation of GSK-3β blunts IPC and Ipost’s
myocardial protection really needs to be investigated [83, 85,
86].
To date, studies have demonstrated a decreased protective
effectofIPConAMIindiabeticsubjects[43, 44, 83, 85–
87]. It is clear that IPC produces myocardial protection
by phosphorylation of GSK-3β that inhibited the opening
of mPTP, but the activity of GSK-3β was found to be
elevated during diabetes [21, 23, 35, 63]. Yadav et al.
[44] investigated the role of GSK-3β in attenuating the
cardioprotective effect of IPC using a ty pe-1diabetic rat
model. They found that IPC had protective effect on
normal rat myocardium, but this cardioprotective effect
of IPC was significantly attenuated in diabetic rat. At the
same time, they found that GSK-3β inhibitors, including
lithium chloride, indirubin-3 monooxime, and SB216763,
significantly reduced the myocardial damage and decreased
infarct size in diabetic rat myocardium. This study suggests
that diabetes-induced attenuation of myocardial protection
mediated by IPC involves in the activation of GSK-3β.In
addition, Ghaboura et al. [43] also demonstrated that the
attenuation of EPO-mediated myocardial protection from
ischemia/reperfusion under diabetic condition was related
to the decrease in EPO-stimulated GSK-3β phosphorylation.
The administration of GSK-3β inhibitor SB216763 protected
the hearts from ischemia/reperfusion-induced damage in
control and diabetic g roups [43]. Therefore, the inhibition
of IPC myocardial protection in the diabetes is most likely
related to the activation of GSK-3β [43, 44].
Because Ipost and IPC share some common signal
transduction cascades proposed above (Figure 2
), which
include the activation of survival protein kinase pathways
[13]. In the study by Drenger et al. [81], they demonstrated
that diabetes can impair the protective effect of Ipost on
myocardial damage or infarction through inhibition of STAT
3-mediated PI3K/Akt pathways. Up to now, there remains
no proof to indicate that diabetes can inhibit the protective
effect of Ipost on the myocardium; therefore, it remains to be
further explored.
5. Is It Possible to Prevent
the Diabeti c Inhibition of IPC or
Ipost Myocardial Protection against
Ischemia/Reperfusion Injury?
We have demonstrated that diabetes-induced myocardial
oxidative damage and inflammation mainly due to the
activation of GSK-3β. When we inactivated GSK-3β activ-
ity with its inactivator in diabetic mice, diabetes-induced
myocardial damage were almost completely prevented [63].
In addition, we have discussed above that inactivation
of GSK-3β w ith its specific inactivators can also directly
afford the myocardial protection in diabetic animals treated
with GSK-3β inactivators [43, 44]. Therefore, any reagents
that can inactivate GSK-3β may have the potential to be
applied for the prevention of diabetic inhibition of IPC-
and/or Ipost-mediated myocardial protection. Except for the
consideration of GSK-3β inhibitors as discussed above and
also listed in the Table 1, the following reagents (Table 1)may
also have such potential.
Zinc (Zn) is an interesting candidate because Zn is an
important trace element found in most body tissues as
bivalent cations and has essential roles in human health.
Zn has also an insulin-like function that was found also
to be related to its inactivation of GSK-3β [88]. We have
demonstrated that Zn supplementation to diabetic mice
could significantly prevent the development of myocardial
oxidative damage, remodeling, and dysfunction in these
diabetic mice [ 64]. Although we did not explore whether
the myocardial protection by Zn supplementation in these
diabetic mice is mediated by the inactivation of GSK-3β
by supplied Zn, other studies have reported that Zn also
inactivated GSK-3β in several conditions. In the experiment
from Chanoit et al. [42], for instance, they found that the
treatment of myocardial H9c2 cells with ZnCl
2
(10 μM) for
20 min significantly enhanced GSK-3β phosphorylation at
6 Experimental Diabetes Research
Ser9, indicating that exogenous Zn can inactivate GSK-3β in
H9c2 ce lls. Other experiments [41] also demonstrated that
Zn also increased mitochondrial GSK-3β phosphorylation.
This may indicate an involvement of the mitochondria in the
action of Zn.
Zn applied at reperfusion period reduced cell death in
the cells subjected to ischemia/reperfusion, which confirmed
thatZnmayactasaninactivatorofGSK-3β to provide a
myocardial protection at reperfusion [41, 42, 89]. Besides
the direct inactivation of GSK-3β, Zn was also reported to
stimulate Akt phosphorylation by inhibiting Akt negative
regulators, including phosphatase and tensin homologue on
chromosome 10 (PTEN) and protein tyrosine phosphatase
1B (PTP1B) [65–67]. Inactivation of PTEN and/or PTP1B
may also contribute to Zn’s inac tivation of GSK-3β via Akt
activation [41]. Therefore, Zn may inhibit GSK-3β by direct
and indirect mechanisms to protect the myocardium from
diabetic activation of GSK-3β-mediated pathogenic effects.
In addition to Zn protective effects, other substrates
are also reported to exert their protective effect, as IPC
and Ipost, on ischemia/reperfusion-induced cardiac damage.
For instance, adenosine leads to the activation and/or
translocation of PKC, PI3K, and mitogen-activated protein
kinase (MAPK) and, subsequently, affords IPC- or Ipost-
like myocardial protection at the level of mitochondrial
targets [68]. Endogenous opioids have also been documented
to be involved in protective effects of Ipost [69, 70].
The administration of EPO at the time of reperfusion
afforded a beneficial effect on Ipost myocardial prote ction
in rabbits [90]andmice[73]. EPO administration just
prior to reperfusion has reduced infarct size in isolated rat
and dog hearts, and even in canine hearts. Furthermore,
EPO administration even 5 min after the reperfusion has
also provided protective responses [74, 91]. Lamont et al.
reported that both melatonin and resveratrol, as found in
red wine, protected the myocardium in an experimental
model from myocardial infarction via the survivor activating
factor enhancement pathway [92]. Fang et al. demonstrate
that sevoflurane administered immediately during early
reperfusion prevented the myocardial infarction [75].
Although all these substances can afford myocardial
protective effects on ischemia/reperfusion in the models
without diabetes, whether these substances can modify
diabetic individuals to maintain the myocardial protection
of IPC and Ipost remains to be explored in the future
studies.
6. Conclusion
Epidemiological data show that diabetes is a major risk
for cardiovascular diseases and the mortality of diabetic
patients with acute myocardial infarction is 2–6 folds higher
than that of nondiabetic patients with the same myocardial
infarction. The poor prognosis may be at least in part because
of diabetic inhibition of IPC- and Ipost-mediated pro-
tective mechanisms against ischemia/reperfusion injuries.
Emerging evidence indicates that both IPC- and Ipost-
mediated myocardial protection pre dominantly be mediated
by stimulating PI3K/Akt and associated GSK-3β pathway
while diabetes-mediated pathogenic effects are found to be
mediated by inhibiting PI3K/Akt and associated GSK-3β
pathway. Therefore, diabetic inhibition of IPC- and Ipost-
mediated myocardial protection may be mediated by the
activation of GSK-3β pathway, which suggests a possibility
that we may activate PI3K/Akt indirectly to inactivate GSK-
3β pathway or use GSK-3β inactivator directly to inactive
GSK-3β pathway to preserve IPC- and/or Ipost-mediated
myocardial protection under diabetic conditions. Although
there is not enough experimental and epidemiological
evidence to support our assumption, it was worthy to be
explored in the future studies.
Acknowledgment
The studies cited from the authors laboratories in the article
were supported in part by Basic Science Award from ADA
(01-11-BS-17 to LC), and a 50101 project from the First
Hospital of Jilin University (To LC).
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