(Circulation. 2000;101:660.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart
From the Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass (Y.F., T.N., K.W.), and the Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, Bronx, NY (D.W., R.N.K.).
Correspondence to Dr Kenneth Walsh, Division of Cardiovascular Research, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail kwalsh{at}opal.tufts.edu
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Abstract |
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Background—IGF-1 has been shown to protect myocardium against death in animal models of infarct and ischemia-reperfusion injury. In the present study, we investigated the role of the IGF-1–regulated protein kinase Akt in cardiac myocyte survival in vitro and in vivo.
Methods and Results—IGF-1 promoted survival of cultured cardiomyocytes under conditions of serum deprivation in a dose-dependent manner but had no effect on cardiac fibroblast survival. The cytoprotective effect of IGF-1 on cardiomyocytes was abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin. Wortmannin had no effect on cardiomyocyte viability in the absence of IGF-1. IGF-1–mediated cytoprotection correlated with the wortmannin-sensitive induction of Akt protein kinase activity. To examine the functional consequences of Akt activation in cardiomyocyte survival, replication-defective adenoviral constructs expressing wild-type, dominant-negative, and constitutively active Akt genes were constructed. Transduction of dominant-negative Akt blocked IGF-1–induced survival but had no effect on cardiomyocyte survival in the absence of IGF-1. In contrast, transduction of wild-type Akt enhanced cardiomyocyte survival at subsaturating levels of IGF-1, whereas constitutively active Akt protected cardiomyocytes from apoptosis in the absence of IGF-1. After transduction into the mouse heart in vivo, constitutively active Akt protected against myocyte apoptosis in response to ischemia-reperfusion injury.
Conclusions—These data are the first documentation that Akt functions to promote cellular survival in vivo, and they indicate that the activation of this pathway may be useful in promoting myocyte survival in the diseased heart.
Key Words: myocytes • apoptosis • Akt • ischemia • reperfusion
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Introduction |
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Myocyte loss, both necrotic and apoptotic, is a feature of many heart pathological conditions.1 Because adult cardiomyocytes possess minimal capacity to reenter the cell cycle,2 3 the control of myocyte loss through suppression of cell death pathways represents a logical strategy to prevent heart failure.4 5 It has been shown that transgenic mice overexpressing insulin-like growth factor-1 (IGF-1) display less myocyte apoptosis after myocardial infarction and have reduced wall stress and ventricular dilatation.6 IGF-1 administered to rats also reduces myocardial apoptosis and injury in response to ischemia followed by reperfusion.7 More recently, it has been shown that IGF-1 functions as a cell survival factor for cultured cardiac myocytes exposed to doxorubicin in the absence of serum.8 Therefore, analysis of the IGF-1 signaling pathways, especially with respect to cell survival, may lead to the development of clinical strategies to treat heart disease.
IGF-1 stimulates several signaling pathways, including phosphatidylinositol (PI) 3-kinase.9 Likewise, PI 3-kinase has a number of downstream targets, including the Akt proto-oncogene,10 a serine/threonine protein kinase that is activated by the inositol lipid products of the PI 3-kinase reaction.11 Activation of Akt has been shown to promote survival of some cell types, including neurons and lymphocytes.11 In other cell types, however, activation of Akt or inhibition of PI 3-kinase has no effect on survival.12 Here, we investigated the role of PI 3-kinase–dependent activation of Akt in IGF-1–mediated cardiomyocyte survival in culture and tested whether constitutive activation of Akt could protect myocytes in vivo from reperfusion injury.
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Methods |
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Reagents, Cell Culture, and Akt Assays
IGF-1 was purchased from Gibco BRL. Wortmannin was obtained from Sigma. Anti-Akt antibody and its corresponding immunogenic peptide came from Santa Cruz Biotechnology. Anti-hemagglutinin (HA) antibodies were from Boehringer Mannheim or Santa Cruz. Anti–ß-galactosidase antibody was from Chemicon. Protein G-agarose was purchased from Boehringer Mannheim. Peroxidase-conjugated anti-mouse IgG was obtained from Amersham Life Science. Primary cultures of neonatal cardiac myocytes were prepared as described previously.9 Cultures were enriched with cardiac myocytes by preplating for 60 minutes to eliminate fibroblasts. More than 90% of the cells were identified as cardiac myocytes by immunocytochemistry with anti-sarcomeric
-actin (Sigma). Attached cells were passaged
once and used as the fibroblast fraction. Cell viability was determined
with the trypan blue exclusion assay.13 Surviving cell
number is expressed relative to the initial cell number. Alternatively,
cells were scored for condensed or pyknotic nuclei after fixation in
3.7% formaldehyde and staining with Hoechst 33342. In some assays,
cells were pretreated with wortmannin for 30 minutes and incubated in
the medium containing wortmannin in the presence or absence of IGF-1.
Dimethyl sulfoxide was used as the vehicle for the wortmannin at a
concentration of 0.1% (vol/vol). Control cultures received the vehicle
alone. Akt kinase assays were performed on anti-Akt or anti-HA
immunoprecipitates from cell lysates as described previously with
histone H2B.13 Immunoblots were performed as
described previously.14
DNA Ladder and TUNEL Analyses With Cultured
Myocytes
DNA ladder experiments were performed as described
previously.15 In brief, DNA was purified by the NaI method
after treatment with proteinase K and RNase A. DNA (10 µg) was
separated on agarose gel electrophoresis. For immunofluorescent
microscopy, cells were fixed with 3.7% formaldehyde in PBS for 20
minutes. After 2 washes with PBS, cells were
permeabilized with 0.2% Triton X-100 and washed 3 more
times with PBS. After incubation with the first antibody
(anti–-sarcomeric actin, Sigma) at 37°C for 60 minutes, cells
were washed 3 times in PBS, then incubated with secondary antibody
(rhodamine-labeled anti-mouse IgG, Pierce) at 37°C for 60 minutes.
This was followed by staining with Hoechst 33342. Finally, terminal
deoxynucleotidyl transferase (TdT)–mediated dUTP
nick end-labeling (TUNEL) staining was performed for detection of
apoptotic cells according to the manufacturer’s protocol
(Boehringer).
Adenoviral Constructs
Wild-type, dominant-negative, and constitutively active forms of
murine Akt tagged with the HA epitope were constructed as
described previously.16 The dominant-negative
Akt mutant (Adeno-dnAkt) has alanine residues substituted
for threonine at position 308 and serine at position 473. The
constitutively active Akt (Adeno-myrAkt) has the
c-src myristoylation sequence fused in frame to the
N-terminus of the wild-type Akt coding sequence that targets
the fusion protein to the membrane. Viral vectors expressing wild-type
(wtAkt) or mutant Akt genes or lacZ (Adeno-ßgal) from the
CMV promoter were purified by CsCl ultracentrifugation.
Myocytes were plated in M199 containing 10% FCS overnight and then
incubated with adenovirus vector at a multiplicity of infection (MOI)
of 25 in M199 containing 2% FCS. After an overnight incubation, the
virus was removed and cells were cultured in serum-free M199.
Adenovirus Transduction In Vivo, Transgene Detection, TUNEL, and
Evans Blue Staining
Eleven C57BL/6J mice 6 to 8 weeks old were anesthetized
with methoxyflurane and ventilated with a rodent respirator attached to
a nose cone. A mixture of Adeno-myrAkt (6x107
pfu/mouse) plus Adeno-ßgal (1x107 pfu/mouse)
or Adeno-ßgal (7x107 pfu/mouse) alone in 15
µL of PBS with 10% glycerol was quickly injected into the apex and
anterolateral wall of the heart with a 26-gauge needle.17
Twenty hours later, animals were subjected to sham operation or left
coronary artery occlusion for 45 minutes, followed by 4 hours
of reperfusion. Hearts were frozen immediately after euthanasia, and
10-µm sections were prepared with a Microm HM505E (Zeiss). Sections
were fixed with 4% paraformaldehyde in PBS for 15
minutes and stained with Hoechst 33342 and anti-HA or
anti–ß-galactosidase antibody. The same sections were also stained
with TUNEL to detect apoptotic cells according to the
manufacturer’s protocol (Boehringer). Secondary antibodies
labeled with rhodamine (Pierce) were used for the detection of
HA-Akt–positive or ß-galactosidase–positive cells. Myocyte identity
was indicated by staining with anti–-sarcomeric actin antibody, by
use of Cy5-labeled secondary antibody (Accurate Chemical and Scientific
Corp). Alternatively, sections were stained with X-gal. For animals
subjected to ischemia-reperfusion injury, sections
corresponding to the left ventricular free wall were
analyzed by first viewing the fluorescein channel
to locate the region of injury as indicated by TUNEL-positive nuclei.
TUNEL-positive microscopic fields were then assessed for cells staining
positive for HA-Akt or ß-galactosidase transgenes. Once
transgene-positive high-power fields (x400) were identified, all
myocytes within the field (
200) were scored for transgene expression
and TUNEL staining. Two or 3 randomly chosen transgene-positive,
high-power fields were examined for each mouse. The percentages of
transgene-positive and -negative myocytes that were TUNEL-positive were
compared in each group to assess whether adenovirus-mediated
myrAkt gene delivery inhibited
ischemia-reperfusion–induced myocyte apoptosis in
vivo. For sham-operated animals, sections of the left
ventricular wall were first scored for HA-tagged Akt, then
for TUNEL staining in sections corresponding to the left
ventricular free wall. A separate group of mice was
subjected to sham operation, coronary occlusion, or
coronary occlusion followed by reperfusion. Regions of
myocardial perfusion under each condition were assessed by staining
with Evans blue dye (Sigma) as described
previously.18
Statistical Analysis
All data were evaluated with a 2-tailed, unpaired Student’s
t test and expressed as the mean±SEM. A value of
P<0.05 was considered significant.
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Results |
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IGF-1 Protects Cardiac Myocytes Under Conditions of Serum Deprivation
Serum deprivation induces apoptosis in cultured cardiomyocytes.8 19 To document the cytoprotective effects of IGF-1 under the conditions of our assays, neonatal rat cardiac myocytes were cultured in serum-free medium in the presence or absence of IGF-1, and cell viability was determined by trypan blue exclusion at various time points (Figure 1A
). In the absence of IGF-1, cardiac
myocyte cultures displayed a time-dependent decrease in viability with
>50% loss of live cells by 72 hours. However, cardiac myocyte
viability was maintained in the presence of IGF-1. In contrast to the
myocyte fraction of cells, passaged nonmyocyte cells
(fibroblasts) prepared from neonatal heart were resistant to
death induced by serum deprivation (Figure 1B). The
insensitivity of cardiac fibroblasts to serum
deprivation–induced cell death has been reported
previously.19 Cardiomyocyte protection was dependent on
the dose of IGF-1 (Figure 1C). IGF-1–induced cytoprotection was
abrogated by treatment with 200 nmol/L wortmannin (Figure 1D),
suggesting that the survival effects of IGF-1 are regulated by effector
proteins downstream of PI 3-kinase. In the absence of IGF-1, wortmannin
had no effect on cardiomyocyte viability. To provide
additional evidence that these treatments influence cell death,
cultures were fixed and stained with Hoechst 33342 to assay for
chromosomal condensation, one indicator of apoptosis. IGF-1
suppressed the incidence of pyknotic nuclei, and this effect was
reversed by the inclusion of wortmannin in the culture medium (not
shown).
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) 50 ng/mL of IGF-1 under
serum-deprivation conditions for the indicated times, and
surviving cells were counted by the trypan blue exclusion assay. B,
IGF-1 has no effects on the viability of nonmyocyte cells under
serum-depleted conditions. Serum-deprived non–cardiac myocyte culture
was incubated in the presence (+) or absence (-) of IGF-1 (50 ng/mL)
for 72 hours, and viable cells were counted by trypan blue exclusion
assay. C, IGF-1 promotes myocyte survival in a dose-dependent manner.
Cardiac myocytes were cultured with the indicated concentrations of
IGF-1 in the serum-deprivation medium for 72 hours, and
cell viability was determined by trypan blue exclusion assay. D,
IGF-1–mediated myocyte survival is inhibited by wortmannin. Cardiac
myocytes were cultured in presence of indicated concentrations of
wortmannin (Wort) with or without IGF-1 (50 ng/mL) for 72 hours, and
surviving cell number was analyzed by trypan blue methods. All
assays were performed in quadruplicate, and data are shown as
mean±SEM.
Wortmannin-Sensitive Activation of Akt by IGF-1
Akt activity was determined in cultures of serum-deprived cardiac
myocytes in the presence or absence of IGF-1. Akt protein kinase
activity was assessed in immunoprecipitates of lysates of cultured
cardiomyocytes with an antibody that reacts specifically
with Akt but not Akt2, which is also expressed in the
heart.20 Immunoprecipitated Akt activity was assayed with
histone H2B as substrate. In addition, cell lysates were
immunoprecipitated with anti-Akt antibody in the presence or absence of
the immunogenic competitor peptides. Akt-associated
phosphorylation of histone H2B was induced by IGF-1
(Figure 2A). The IGF-1–induced kinase
activity was largely attributable to Akt, because kinase activity was
reduced when lysates were immunoprecipitated in the presence of the
immunogenic competitor peptide. The effect of wortmannin on
IGF-1–induced Akt activity was also analyzed. Inclusion of 200
nmol/L wortmannin in the culture medium completely blocked
IGF-1–activated Akt kinase activity (Figure 2B). These
data suggest that Akt acts downstream of PI 3-kinase in response to
IGF-1 in cardiomyocytes.
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Adenoviral Transfection of Wild-Type, Dominant-Negative, or
Constitutively Active Akt in Cultured Cardiomyocytes
To determine the functional significance of Akt activation in
IGF-1–stimulated cardiac myocyte cultures, replication-defective
adenoviral vectors expressing wild-type and mutant forms of Akt fused
to the HA epitope were constructed (Figure 3A). The mutant Akt (T308A, S473A) cannot
be activated by phosphorylation,21
and it functions in a dominant-negative manner.22 Cardiac
myocytes were infected overnight with adenovirus vectors at an MOI of
25, and expression of exogenous Akt proteins was demonstrated by
Western immunoblot analysis with anti-HA antibody
(Figure 3B). To analyze the kinase activities of
adenovirally encoded Akt proteins, parallel serum-deprived cultures
were incubated in the presence or absence of IGF-1. Specific Akt
protein kinase activity was detected in extracts from cells infected
with the wild-type Akt vector in the presence, but not the absence, of
IGF-1 stimulation (Figure 3C). The vector expressing
dominant-negative Akt was inactive with regard to kinase activity. In
contrast, cells infected with the vector expressing constitutively
active Akt displayed high levels of kinase activity in the presence or
absence of IGF-1.
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Cardiac myocyte cultures were infected with an adenoviral vector
expressing dominant-negative Akt mutant to test whether Akt is
essential for IGF-1–mediated survival. Infection with the
dominant-negative Akt vector largely eliminated the increase in cell
survival resulting from the inclusion of 25 or 50 ng/mL IGF-1 in the
culture medium (Figure 4A). In the
absence of IGF-1, Adeno-dnAkt did not affect cardiomyocyte
survival, indicating the specificity of dnAkt action. The control
adenoviral construct expressing ß-galactosidase (Adeno-ßgal) had no
detectable effect on myocyte viability. Furthermore, infection with
Adeno-ßgal did not affect Akt activity in cardiomyocytes
(data not shown).
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) or
infected with adenovirus vector expressing dnAkt (•) or ß-gal
(
). Cells were cultured in indicated concentrations of IGF-1 for 72
hours, and cell viability was analyzed by trypan blue exclusion
assay. Assays were performed in quadruplicate, and data are
demonstrated as mean±SEM (*P<0.05). B, Overexpression
of wild-type Akt facilitates myocyte survival in response to IGF-1.
Cells were mock-infected (solid columns) or infected with ß-gal
(shaded columns) or wtAkt (open columns). Parallel cultures were
incubated in serum-free medium in presence or absence of 12.5 ng/mL
IGF-1 for 72 hours. Viable cell number was determined by trypan blue
exclusion assays. Assays were performed in quadruplicate, and data are
shown as mean±SEM (*P<0.05). C, Constitutively active
Akt protects cardiomyocytes from apoptosis. Cardiac
myocytes were transfected with ß-gal or constitutively active Akt
(myrAkt). Cells were cultured in serum-deprived condition for 48 hours,
and DNA fragmentation was analyzed. M indicates marker of
123-bp DNA ladder.
To investigate the consequences of Akt overexpression on myocyte
survival, cells were transfected with adenoviral vectors expressing
wild-type Akt or ß-galactosidase and cultured without serum in the
absence or presence of IGF-1. Overexpression of wild-type Akt had no
significant effect on survival in the absence of IGF-1, but cell
survival was promoted by Akt overexpression in the presence of a
subsaturating concentration of IGF-1 (Figure 4B
). At higher
IGF-1 concentrations, overexpression of Akt had little or no effect on
cell viability (not shown). These data show that Akt gene
transfer enhances the survival effects of IGF-1, indicating that Akt is
a critical factor in survival of cardiac myocytes under these
conditions.
The effects of constitutively active Akt on cardiomyocyte
cultures were also assessed. Infection with Adeno-myrAkt produced
cell-shape changes similar to those reported in stably transfected PAE
cells.23 These cell-shape changes obscured assessments of
viability with the trypan blue exclusion assay or staining with Hoechst
33342 to detect nuclear condensation. Thus, DNA fragmentation was
assessed in cultures infected with Adeno-myrAkt or the control vector
Adeno-ßgal. DNA prepared from serum-deprived
cardiomyocyte cultures infected with Adeno-ßgal displayed
the nucleosome spacing ladder after gel electrophoresis that is
indicative of apoptosis (Figure 4C). This DNA ladder was
diminished, but not eliminated, in serum-deprived cultures infected
with Adeno-myrAkt, suggesting that this agent inhibits
apoptotic cell death in the absence of exogenous IGF-1
stimulation.
TUNEL analyses were performed to examine the effects of the
different Akt-expressing adenovirus vectors on
cardiomyocyte survival in vitro. Cells were infected with
the indicated adenovirus vector or mock-infected overnight, and then
cultured in the serum-depleted medium in the presence of the indicated
concentrations of IGF-1 for 48 hours (Figure 5). Apoptotic cells were
identified by TUNEL and Hoechst staining, and staining with
anti–-sarcomeric actin was performed to confirm myocyte identity
(Figure 5A). As shown in Figure 5B, increasing
concentrations of IGF-1 reduced the frequency of myocyte
apoptosis in mock- and Adeno-ßgal–transfected cells.
Infection with adenovirus expressing dominant-negative Akt blocked the
protective effects of IGF-1. Infection with adenovirus expressing
wild-type Akt facilitated IGF-1–mediated cardiomyocyte
survival at low IGF-1 concentrations, whereas infection with adenovirus
expressing constitutively active Akt reduced the frequency of myocyte
apoptosis in the absence of IGF-1 or at low concentrations of
IGF-1. Of note, Adeno-myrAkt did not have an additive effect on
survival at saturating IGF-1 (50 ng/mL), suggesting further that Akt
activation is an integral feature of the IGF-1 survival pathway in
cardiomyocytes.
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Constitutively Active Akt Protects Myocardium From
Apoptosis After Reperfusion Injury
Reperfusion of ischemic myocardium is reported
to accelerate myocyte apoptosis,24 and IGF-1 can
protect myocardium under these conditions.7
Thus, we investigated whether expression of constitutively active Akt
could protect murine myocardium from reperfusion injury
(Figure 6A). In this model, adenoviral
constructs were injected directly into the apical and anterolateral
free wall of the heart, a region that shows a large perfusion defect
after occlusion of the left coronary artery as determined by
staining with Evans blue dye (Figure 6B). Evans blue staining
was uniform after removal of the ligature, consistent with
restored perfusion (not shown). Direct adenovirus injection resulted in
transgene expression localized to cells adjacent to the track of the
needle and confined to myocardium subject to hypoperfusion
(Figure 6C). To examine the effects of constitutive Akt
expression on myocyte viability in vivo, mouse hearts were injected
with Adeno-myrAkt or the Adeno-ßgal control vector 20 hours before
ischemia-reperfusion injury or sham operation. Sections of
heart were analyzed for transgene expression by
immunohistochemical detection of the HA epitope (myrAkt) or
ß-galactosidase, and cell death was assessed by TUNEL staining
(Figure 6D and 6E). Cells with apoptotic nuclei were
identified as cardiac myocytes by staining with anti–-sarcomeric
actin antibody (not shown). High-power microscopic fields (200
Hoechst-positive myocytes per field) were identified that contained
transgene-positive cells. Systematic analyses of these fields
revealed that myocardial cells expressing HA-tagged myrAkt displayed
significantly fewer TUNEL-positive nuclei than immediately adjacent
cells that were negative for transgene expression (Figure 6F).
In contrast to cultured myocytes, no obvious morphological alterations
were apparent in the cells expressing myrAkt (not shown). Mouse hearts
injected with Adeno-ßgal and subjected to
ischemia-reperfusion injury displayed no differences in
TUNEL-positive staining between cells that were positive or negative
for ß-galactosidase transgene expression (Figure 6F).
TUNEL-positive cells were not identified in either HA-myrAkt–positive
or –negative cells of sham-operated animals.
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Discussion |
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Here, we report that IGF-1–mediated survival correlates with the wortmannin-sensitive activation of the protein kinase Akt in cultured cardiomyocytes. The functional significance of Akt activation was demonstrated by use of adenovirus-mediated transfer of wild-type and mutant Akt genes to cardiomyocytes. Dominant-negative Akt abolished IGF-1–mediated cardiac myocyte survival, whereas overexpression of wild-type or constitutively active Akt genes promoted cardiac myocyte survival. These data suggest that the PI 3-kinase–dependent activation of Akt is a key step in the IGF-1 signaling pathway that protects cardiomyocytes from death.
Previous studies have shown that permanent or temporary occlusion of the left coronary artery of the mouse results in myocyte apoptosis exclusively in the left ventricular free wall.7 18 24 Thus, we reasoned that the direct injection of the adenovirus expressing constitutively active Akt could minimize myocyte apoptosis in the affected region of the heart. Furthermore, because adenovirus-mediated gene transfer permits acute delivery of recombinant protein, we reasoned that this model would provide a more direct test of protein function than transgenic animals, in which secondary effects of chronic expression can confound analyses. After ischemia-reperfusion injury, the numbers of TUNEL-positive myocyte nuclei in myocardial cells expressing constitutively active Akt were decreased compared with adjacent, nontransduced myocardial cells. Furthermore, the observed decrease in cell death could be attributed to the Akt transgene, because hearts injected with Adeno-ßgal revealed no difference in frequency of TUNEL staining in the ß-galactosidase–positive and –negative cells. Although serum deprivation in vitro simulates a component of ischemia, ischemia-reperfusion is a more complex stimulus, involving deprivation of growth/survival factors, accumulation of metabolic waste products, changes in mechanical factors, and generation of toxic substances, such as reactive oxygen species.1 4 6 7 Our finding that Akt inhibits myocyte death induced not only by serum deprivation but also by ischemia-reperfusion in vivo suggests that this protein lies at the crossroads of multiple apoptotic stimuli activated during myocardial injury.
Signaling pathways that may also converge on Akt include the cardiomyocyte survival factors that function through the glycoprotein 130 (gp130) signal-transducing protein. For example, CT-119 and LIF25 can activate Akt in a wortmannin-sensitive manner,26 but the role of Akt in gp130-mediated survival has yet to be demonstrated. It might also be relevant that insulin administered with glucose and potassium (GIK therapy) can slow the rate of ischemic cell death after acute myocardial infarction, thereby reducing patient mortality.27 Like IGF-1, insulin can activate Akt through its interaction with the IGF-1 receptor.21 Therefore, Akt may function at a nodal point to coordinate growth factor signaling with myocyte survival and thus may represent a logical target for pharmacological or genetic therapies to promote myocyte survival during heart failure.
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Acknowledgments |
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This work was supported by NIH grants AG-15052, HL-50692, and AR-40197 to Dr Walsh and HL-60665 and HL-61550 to Dr Kitsis. Dr Kitsis is the Charles and Tamara Krasne Faculty Scholar in Cardiovascular Research of the Albert Einstein College of Medicine. Dr Fujio is supported by the Study Group of Molecular Cardiology.
Received June 18, 1999; revision received August 10, 1999; accepted August 16, 1999.
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B. J. Davis, Z. Xie, B. Viollet, and M.-H. Zou Activation of the AMP-Activated Kinase by Antidiabetes Drug Metformin Stimulates Nitric Oxide Synthesis In Vivo by Promoting the Association of Heat Shock Protein 90 and Endothelial Nitric Oxide Synthase Diabetes, February 1, 2006; 55(2): 496 - 505. [Abstract] [Full Text] [PDF]
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S. Miyamoto, A. L. Howes, J. W. Adams, G. W. Dorn II, and J. H. Brown Ca2+ Dysregulation Induces Mitochondrial Depolarization and Apoptosis: ROLE OF Na+/Ca2+ EXCHANGER AND AKT J. Biol. Chem., November 18, 2005; 280(46): 38505 - 38512. [Abstract] [Full Text] [PDF]
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Y.-T. Tseng, N. Yano, A. Rojan, J. P. Stabila, B. G. McGonnigal, V. Ianus, R. Wadhawan, and J. F. Padbury Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute {beta}-adrenergic stimulation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1834 - H1842. [Abstract] [Full Text] [PDF]
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A. Kher, K. K. Meldrum, M. Wang, B. M. Tsai, J. M. Pitcher, and D. R. Meldrum Cellular and molecular mechanisms of sex differences in renal ischemia-reperfusion injury Cardiovasc Res, September 1, 2005; 67(4): 594 - 603. [Abstract] [Full Text] [PDF]
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C. Kupatt, R. Hinkel, M. Lamparter, M.-L. von Bruhl, T. Pohl, J. Horstkotte, H. Beck, S. Muller, S. Delker, F.-J. Gildehaus, et al. Retroinfusion of Embryonic Endothelial Progenitor Cells Attenuates Ischemia-Reperfusion Injury in Pigs: Role of Phosphatidylinositol 3-Kinase/AKT Kinase Circulation, August 30, 2005; 112(9_suppl): I-117 - I-122. [Abstract] [Full Text] [PDF]
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J. F. Grehan, B. K. Levay-Young, J. L. Fogelson, V. Francois-Bongarcon, B. A. Benson, and A. P. Dalmasso IL-4 and IL-13 Induce Protection of Porcine Endothelial Cells from Killing by Human Complement and from Apoptosis through Activation of a Phosphatidylinositide 3-Kinase/Akt Pathway J. Immunol., August 1, 2005; 175(3): 1903 - 1910. [Abstract] [Full Text] [PDF]
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F. Dong, L. B. Esberg, Z. K. Roughead, J. Ren, and J. T. Saari Increased contractility of cardiomyocytes from copper-deficient rats is associated with upregulation of cardiac IGF-I receptor Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H78 - H84. [Abstract] [Full Text] [PDF]
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W. Chao, Y. Shen, X. Zhu, H. Zhao, M. Novikov, U. Schmidt, and A. Rosenzweig Lipopolysaccharide Improves Cardiomyocyte Survival and Function after Serum Deprivation J. Biol. Chem., June 10, 2005; 280(23): 21997 - 22005. [Abstract] [Full Text] [PDF]
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E. R. Gross, J. N. Peart, A. K. Hsu, J. A. Auchampach, and G. J. Gross Extending the cardioprotective window using a novel {delta}-opioid agonist fentanyl isothiocyanate via the PI3-kinase pathway Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2744 - H2749. [Abstract] [Full Text] [PDF]
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T. Aoyama, T. Matsui, M. Novikov, J. Park, B. Hemmings, and A. Rosenzweig Serum and Glucocorticoid-Responsive Kinase-1 Regulates Cardiomyocyte Survival and Hypertrophic Response Circulation, April 5, 2005; 111(13): 1652 - 1659. [Abstract] [Full Text] [PDF]
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A. Pfosser, M. Thalgott, K. Buttner, A. Brouet, O. Feron, P. Boekstegers, and C. Kupatt Liposomal Hsp90 cDNA induces neovascularization via nitric oxide in chronic ischemia Cardiovasc Res, February 15, 2005; 65(3): 728 - 736. [Abstract] [Full Text] [PDF]
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C. L. Murriel, E. Churchill, K. Inagaki, L. I. Szweda, and D. Mochly-Rosen Protein Kinase C{delta} Activation Induces Apoptosis in Response to Cardiac Ischemia and Reperfusion Damage: A MECHANISM INVOLVING BAD AND THE MITOCHONDRIA J. Biol. Chem., November 12, 2004; 279(46): 47985 - 47991. [Abstract] [Full Text] [PDF]
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G. C. Sparagna, C. E. Jones, and D. L. M. Hickson-Bick Attenuation of fatty acid-induced apoptosis by low-dose alcohol in neonatal rat cardiomyocytes Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2209 - H2215. [Abstract] [Full Text] [PDF]
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M. Sano and M. D. Schneider Cyclin-Dependent Kinase-9: An RNAPII Kinase at the Nexus of Cardiac Growth and Death Cascades Circ. Res., October 29, 2004; 95(9): 867 - 876. [Abstract] [Full Text] [PDF]
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H. Fujimoto, M. Ohno, S. Ayabe, H. Kobayashi, N. Ishizaka, H. Kimura, K.-i. Yoshida, and R. Nagai Carbon Monoxide Protects Against Cardiac Ischemia--Reperfusion Injury In Vivo via MAPK and Akt--eNOS Pathways Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1848 - 1853. [Abstract] [Full Text] [PDF]
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R. D. Patten, I. Pourati, M. J. Aronovitz, J. Baur, F. Celestin, X. Chen, A. Michael, S. Haq, S. Nuedling, C. Grohe, et al. 17{beta}-Estradiol Reduces Cardiomyocyte Apoptosis In Vivo and In Vitro via Activation of Phospho-Inositide-3 Kinase/Akt Signaling Circ. Res., October 1, 2004; 95(7): 692 - 699. [Abstract] [Full Text] [PDF]
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