(Circulation. 1999;100:2373.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Adenoviral Gene Transfer of Activated Phosphatidylinositol 3'-Kinase and Akt Inhibits Apoptosis of Hypoxic Cardiomyocytes In Vitro
From the Cardiovascular Research Center and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (T.M., L.L., F.d.M., R.J.H., A.R.); the Department of Pharmacology, Columbia University, New York, NY (T.F.F.); and the Laboratory of Biological Chemistry, University of Tokyo, Japan (Y.F.).
Correspondence to Anthony Rosenzweig, MD, Cardiovascular Research Center, MGH-East, 149 13th St, Room 4214, Charlestown, MA 02129. E-mail rosenzweig{at}helix.mgh.harvard.edu
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Abstract |
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Background—The intracellular signaling pathways that control cardiomyocyte apoptosis have not been fully defined. Because insulin-like growth factor-1 (IGF-1) prevents cardiomyocyte apoptosis, we examined the role of its downstream signaling molecules in an in vitro model of hypoxia-induced cardiomyocyte apoptosis.
Methods and Results—Treatment of rat neonatal cardiomyocytes with IGF-1 increased activity of both phosphatidylinositol 3' (PI 3)-kinase and its downstream target, Akt (also known as protein kinase B or PKB). Cardiomyocytes were subjected to hypoxia for 24 hours, and apoptosis was assessed by DNA laddering, TUNEL staining, and ELISA for histone-associated DNA fragments. IGF-1 treatment (100 nmol/L) reduced cardiomyocyte apoptosis, and this effect was inhibited by simultaneous treatment with a PI 3-kinase inhibitor. Cardiomyocytes were infected with either a control adenovirus (Ad.EGFP) or adenoviruses carrying constitutively active forms of PI 3-kinase (Ad.BD110) or Akt (Ad.myr-Akt-HA). Ad.BD110 significantly inhibited apoptosis of hypoxic cardiomyocytes compared with Ad.EGFP (61.0±4.6% less DNA fragmentation than in Ad.EGFP-infected cells, P<0.0001). Ad.myr-Akt-HA even more dramatically inhibited apoptosis of hypoxic cardiomyocytes (90.9±1.4% less DNA fragmentation than in controls, P<0.0001).
Conclusions—IGF-1 activates PI 3-kinase and Akt in cardiomyocytes. Activated PI 3-kinase and Akt are each sufficient to protect hypoxic cardiomyocytes against apoptosis in vitro. Adenoviral gene transfer provides a useful tool for investigating the role of these signaling pathways in cardiomyocyte apoptosis.
Key Words: kinase • viruses • growth substances • signal transduction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cardiomyocyte programmed cell death (apoptosis) has been identified in a wide variety of cardiovascular disorders, including myocardial infarction and heart failure (reviewed in Reference 11 ). Apoptosis is particularly prominent in models of ischemia-reperfusion injury, affecting a significant proportion of cardiomyocytes in the involved area.2 Although apoptosis might appear to be an attractive target for therapeutic intervention, the overall functional contribution of apoptosis to disease progression has not been defined in these conditions. Identifying the intracellular signaling pathways that control apoptosis in cardiomyocytes and developing approaches to modulating these pathways could help clarify their role in experimental models of cardiac disease and potentially lay the foundation for novel therapeutic strategies. The goals of this study were to identify signaling pathways that modulate cardiomyocyte apoptosis in vitro and to examine the ability of somatic gene transfer to manipulate these pathways.
Insulin-like growth factor-1 (IGF-1) blocks apoptosis in many settings,2 3 and this ability is generally dependent on activation of phosphatidylinositol 3' (PI 3)-kinase.4 Recent studies have demonstrated that Akt (also known as protein kinase B or PKB) is the target of PI 3-kinase that is both necessary and sufficient to mediate inhibition of apoptosis in cerebellar neurons.3 Akt can inhibit caspase-mediated cell death through at least 3 mechanisms: phosphorylation of the death agonist Bcl-XL/Bcl-2–associated death promoter (BAD), releasing Bcl-2 family members5 ; direct phosphorylation of caspase-96 ; and phosphorylation of the FKHRL1 transcription factor, blocking Fas ligand expression.7 Therefore, PI 3-kinase appears to be a critical component in a signal transduction pathway mechanistically linking viability factors, such as IGF-1, to caspases through activation of the serine-threonine kinase, Akt.
The ability to manipulate the activity of these molecules in cardiomyocytes would facilitate an examination of their functional effects. Relatively specific pharmacological inhibitors of PI 3-kinase have been identified.8 9 In contrast, no inhibitors of Akt have been discovered to date, nor are there reagents that specifically and effectively activate either PI 3-kinase or Akt. In the present study, we used adenoviral gene transfer to directly examine the role of these molecules in an in vitro model of hypoxia-induced cardiomyocyte apoptosis.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In Vitro Model of Cardiomyocyte Hypoxia
Cardiomyocytes were prepared from 1- to 2-day-old rats by use of the Neonatal Cardiomyocyte Isolation System (Worthington Biochemical Corp), plated in 12-well plates or on glass coverslips in 6-well plates at 1x105 or 5x105 cells/well, respectively, and cultured in RPMI 1640/5% FCS/10% horse serum (HS) for 72 hours before infection. Cells were then incubated in RPMI 1640 alone for 2 hours with or without adenoviral vector, as indicated. An equal volume of RPMI 1640/5% FCS/10% HS was then added to each well, and cells were cultured for an additional 46 hours. For hypoxia, the medium was then changed to serum-free RPMI 1640 saturated with 95% N2/5% CO2, and cells were placed in a 37°C airtight box saturated with 95% N2/5% CO2 for 24 hours. O2 concentrations were <0.1% (Ohmeda oxygen monitor, type 5120). For normoxic controls, culture medium was changed to RPMI 1640/5% FCS/10% HS, and cells were placed in a 37°C/5% CO2 incubator for 24 hours before analysis.
TUNEL Staining
TUNEL staining was performed with the Apoptag kit (Intergen),
according to the manufacturer’s recommendations. Cardiomyocytes were
identified by simultaneous immunostaining
with the anti–sarcomeric 
-actinin monoclonal antibody (mAb) EA-53
(Sigma). To quantify the number of apoptotic
cardiomyocytes, nuclei were counterstained with Hoechst
33258 (Sigma), and the total numbers of nuclei and TUNEL-positive
nuclei were counted in -actinin–positive and –negative cells in 8
to 10 low-power fields in 3 independent experiments. More than 1500
nuclei were counted under both normoxic and hypoxic conditions. These
data are given in the text as the mean±SD.
DNA Fragmentation
Myocytes (1x104) were trypsinized and
resuspended in 0.75 mL of lysis buffer (100 mmol/L Tris-HCl [pH
8.5], 5 mmol/L EDTA, 0.2% SDS, 200 mmol/L NaCl, 100 µg/mL
proteinase K). Cell lysates were incubated at 37°C for 4 hours with
agitation and precipitated with an equal volume of isopropanol (1:1) at
-20°C for 4 to 18 hours, followed by phenol/chloroform extraction
and ethanol precipitation at -80°C for 
15 minutes. Pellets were
washed with 70% ethanol, air-dried, and resuspended in TE buffer
(10 mmol/L Tris-HCl [pH 8.0], 1 mmol/L EDTA). RNase
(Boehringer Mannheim) was added to a final concentration of 10
µg/mL. One microgram of each DNA sample was labeled with 0.5 µCi
[-32P]dCTP (DuPont NEN) in the presence of 5
U of Klenow polymerase (NEB, 10 minutes in NEB Klenow buffer) without
additional unlabeled dNTPs. The reaction was terminated (10 mmol/L
EDTA, 75°C for 10 minutes) and subjected to 1.8% agarose gel
electrophoresis and autoradiography.
Cell Death ELISA
Histone-associated DNA fragments were quantified by ELISA
(Boehringer Mannheim). All cells from each well were collected
by trypsinization and pipetting, pelleted (800 rpm, Sorvall T6000B, 5
minutes), lysed, and subjected to the capture ELISA according to the
manufacturer’s protocol. Data were normalized to the amount of DNA
fragmentation seen with hypoxic Ad.EGFP-transduced
cardiomyocytes. Each experiment was carried out in
triplicate and repeated in 3 independent experiments.
Kinase Assays
PI 3-Kinase
PI 3-kinase activity was measured as described
previously.10 Cell lysates were immunoprecipitated with
either anti-phosphotyrosine mAb (PY20) for endogenous PI
3-kinase activity or anti-myc mAb (Santa Cruz Biotech) for
BD110, which is not recognized by PY20. PI 3-kinase activity was
measured in a reaction mixture containing phosphatidylinositol (Avanti)
and [
-32P]ATP (DuPont NEN). After 5 minutes,
the reaction was stopped by the addition of HCl and chloroform:methanol
and analyzed by thin-layer chromatography. PI
3-kinase activity was detected by the appearance of a specific
radioactive spot corresponding to [32P]PI-3-P.
We also verified that phosphorylation was occurring at
the 3 position by using the specific PI 3-kinase substrate,
PI-4,5-P2 (Sigma) (data not shown).
Akt Assay
Akt kinase assays were performed as described
previously.3 Cell lysates were immunoprecipitated with
anti-Akt1 mAb (Upstate Biotech), used in kinase reactions with histone
H2B (Boehringer Mannheim) as substrate and
[-32P]ATP, and subjected to SDS-PAGE. The
lower-molecular-weight area in the gel (with radiolabeled Histone H2B)
was separated for direct autoradiography. The
higher-molecular-weight area in the gel (with Akt) was transferred to a
membrane for immunoblotting with anti-Akt1 mAb
(Transduction Laboratories).
Immunohistochemistry
Cardiomyocytes were fixed with 10% neutral buffered formalin
(22°C, 5 minutes), permeabilized (-20°C
methanol:acetone [1:1], 10 minutes), and incubated with primary mAb
to c-myc or -actinin (30 minutes, 22°C). Cells were
rinsed in PBS, incubated with anti-mouse IgG (Fab-specific) conjugated
to tetramethylrhodamine (Sigma) (30 minutes, 22°C), and
mounted.
Recombinant Adenoviral Vectors
Three recombinant first-generation type 5 adenoviruses were used
for these studies. Ad.EGFP has been described
previously.11 Ad.BD110 contains the myc-tagged
BD11012 expression cassette in E1 and an
EGFP (Clontech) expression cassette in E3 and was created
through homologous recombination between pÄE1A-CMV-BD110 and
pBHG11-EGFP in 293 cells, as previously described.13
The myr-Akt-HA–expressing adenovirus was constructed by first adding
the src myristoylation signal to a cDNA clone expressing HA
epitope–tagged Akt in pCAV-6, transferring the resulting insert into
pACCMCLPA, and obtaining homologous recombinants through cotransfection
with pJM17 (Microbix Biosystems) in 293 cells. Recombinant plaques were
isolated and propagated in 293 cells, and transgene expression and
appropriate kinase activity were verified in
cardiomyocytes. Viral titer was determined by plaque assay
in 293 cells. Stock titers were 
1010 pfu/mL
for each vector, with a particle/pfu ratio of
102. Wild-type adenovirus contamination was
excluded by the absence of both PCR-detectable E1 sequences
and cytopathic effects on the nonpermissive A549 cell line.
Statistical Analysis
Data are represented as the mean±SEM of 3
independent experiments and were compared by ANOVA. The null hypothesis
was rejected at P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hypoxia-Induced Apoptosis in Cardiomyocytes
Transient hypoxia (24 hours) induced apoptosis that was evident by TUNEL staining, DNA laddering, and ELISA for histone-associated DNA fragments, in agreement with previous reports14 15 16 (Figure 1
).
Colocalization of TUNEL-positive cells with immunohistochemical
staining for sarcomeric -actinin confirmed that the
apoptotic cells were cardiomyocytes, rather than
contaminating fibroblasts (Figure 1A). After hypoxia,
97% TUNEL-positive nuclei localized to -actinin–positive cells and
represented 21±2% of the nuclei in these cells. In
contrast, only 2±1.7% of -actinin–positive cells were
TUNEL-positive in normoxic cultures. Only 3.0±1.2% of the
TUNEL-positive nuclei occurred in the absence of -actinin staining.
Further evidence that cardiomyocytes were the predominant
contributor to the apoptosis observed in this model was
provided by 2 additional experiments in which cultures treated with
BrdU to increase the proportion of
cardiomyocytes16 yielded similar results (data
not shown). Importantly, infection of cardiomyocytes with
recombinant control adenovirus (Ad.EGFP) did not affect
cardiomyocyte apoptosis (Figure 1B and 1C).
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Modulation of Hypoxia-Induced Apoptosis in
Cardiomyocytes
IGF-1 effectively blocked cardiomyocyte
apoptosis, consistent with previous
reports15 (Figure 2a).
Although IGF-1 is a known activator of PI 3-kinase, we
documented that this signaling mechanism was preserved in hypoxic
cardiomyocytes. In hypoxic myocytes, PI 3-kinase was
activated by IGF-1 treatment and significantly though
incompletely inhibited by wortmannin (Figure 2b) and LY294002
(data not shown). Hypoxic cardiomyocytes treated with both
IGF-1 and wortmannin displayed significantly more residual PI 3-kinase
activity than cells treated with wortmannin alone (data not shown). We
tested the hypothesis that the IGF-1 survival benefit was mediated
through PI 3-kinase by treating cultures with both IGF-1 and the
specific PI 3-kinase inhibitors wortmannin and LY294002.
LY294002 significantly inhibited the ability of IGF-1 to prevent
apoptosis in hypoxic cardiomyocytes, and a more
modest effect was seen with wortmannin (Figure 2a). The ability
of LY294002 to inhibit the survival benefit from IGF-1 strongly
suggests that this benefit is mediated, at least in part, through PI
3-kinase. However, the combined treatments generally failed to induce
the same amount of DNA laddering as seen in the hypoxic control cells.
This incomplete restoration of apoptosis may reflect either
incomplete inhibition of PI 3-kinase or the involvement of other
IGF-1–activated signaling mechanisms. Of note, LY294002 and
wortmannin did not significantly affect baseline
cardiomyocyte apoptosis, although in some
experiments DNA laddering under hypoxic conditions appeared to be
modestly increased by PI 3-kinase inhibition (data not shown). Although
these data suggest the involvement of PI 3-kinase activation in the
antiapoptotic effect of IGF-1, we cannot exclude the
possibility that IGF-1 and PI 3-kinase modulate apoptosis
through independent mechanisms by this pharmacological approach.
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To overcome this limitation, we used adenoviral gene transfer to
directly examine the effects of specific signaling molecules. We
constructed a recombinant adenoviral vector carrying a constitutively
active form of PI 3-kinase, BD110.12 BD110 contains the
p110 catalytic domain of PI 3-kinase fused in-frame with the binding
domain (AA 474 to 552) of the regulatory subunit, p85,12
leading to constitutive binding and enzymatic activation. This virus
also encodes an independent expression cassette carrying EGFP that
allows direct identification of transduced cells by
fluorescence microscopy (Figure 3). Infection of
cardiomyocytes with Ad.BD110 conferred activation of both
PI 3-kinase and Akt (Figure 4a and 4b).
Treatment of cardiomyocytes with IGF-1 also
activated Akt (Figure 4b). These results both
established the biological activity of Ad.BD110 and confirmed that Akt
is a downstream target of PI 3-kinase in cardiomyocytes
activated by IGF-1 treatment (Figure 4b). Because Akt is
the PI 3-kinase substrate essential for its survival benefit in other
cells,3 we created a recombinant adenovirus carrying a
constitutively active Akt (myr-Akt). This virus was also able to
mediate robust transgene expression in cardiomyocytes and
increased Akt activity even in the absence of IGF-1 (Figure 4b).
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Infection of cardiomyocytes with Ad.BD110 at a multiplicity
of infection (MOI) of 10 plaque-forming units (pfu)/cell did not affect
survival of unstimulated cells (Figure 5a). Infection at an MOI 50 induced
apoptosis of even unstimulated cardiomyocytes,
suggesting that massive overexpression of this pleiotropic kinase is
not well tolerated (data not shown). However,
cardiomyocytes infected at an MOI of 10 pfu/cell were
substantially protected against hypoxia-induced
apoptosis (61.0±4.6% less DNA fragmentation versus
Ad.EGFP-infected cells, P<0.0001) (Figure 5a). Of
note, at this MOI, virtually all of the cardiomyocytes were
transduced, as evident by EGFP expression. The protection afforded by
Ad.BD110 was abolished by simultaneous treatment with the
PI 3-kinase inhibitor LY294002 (10 µmol/L). These
results demonstrate that PI 3-kinase is sufficient to protect hypoxic
cardiomyocytes against apoptosis in vitro.
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In contrast, Ad.myr-Akt-HA did not increase cardiomyocyte
apoptosis even at an MOI of 80 pfu/cell (Figure 5b
and
data not shown). In hypoxic cultures, Ad.myr-Akt-HA significantly
inhibited hypoxia-induced DNA fragmentation in a dose-dependent
manner at an MOI from 10 to 80 pfu/cell (P<0.0001 for all
versus Ad.EGFP-infected cultures). At an MOI of 80 pfu/cell,
Ad.myr-Akt-HA reduced DNA fragmentation of hypoxic
cardiomyocytes by >90% compared with Ad.EGFP-infected
cells (Figure 5b).
In other cell types, Akt inhibits apoptosis through both direct
and indirect inhibition of caspase activity.5 6 7 To
examine whether caspase inhibition could account for the beneficial
effects of PI 3-kinase or Akt activation on survival of hypoxic
cardiomyocytes, we used the synthetic caspase
inhibitor, z-VAD.fmk. In a dose-dependent manner, z-VAD.fmk
reduced apoptosis of hypoxic cardiomyocytes (Figure 5c). The maximum reduction in cardiomyocyte
apoptosis seen with z-VAD.fmk treatment (93.5±2.0%,
P<0.0001 versus uninfected controls) was comparable to that
seen with Ad.myr-Akt-HA infection and greater than that achieved with
BD110 at an MOI of 10 pfu/cell. Thus, caspase inhibition also blocks
apoptosis of hypoxic cardiomyocytes and is
quantitatively sufficient to account for the myocyte survival benefit
seen with IGF-1 treatment as well as Akt or BD110 expression.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We examined the effects of intracellular signaling molecules downstream of the IGF-1 receptor in an in vitro model of transient cardiomyocyte hypoxia. We found that IGF-1 activates PI 3-kinase and Akt in cardiomyocytes. Pharmacological studies suggested that PI 3-kinase was involved in the ability of IGF-1 to inhibit apoptosis of hypoxic cardiomyocytes, and we used adenoviral gene transfer to directly examine the ability of activated PI 3-kinase or its downstream target, Akt, to modulate apoptosis. Expression of activated forms of either PI 3-kinase or Akt in cardiomyocytes was sufficient to inhibit hypoxia-induced apoptosis in vitro. To the best of our knowledge, this is the first demonstration of a critical role for these signaling molecules in cardiomyocyte survival.
Interestingly, Ad.BD110 only incompletely prevented hypoxia-induced DNA fragmentation at an MOI of 10 pfu/cell and killed cardiomyocytes at high MOI. Incomplete protection could reflect either low transduction efficiency with population heterogeneity, the inability of this signaling pathway to completely protect against apoptosis, or inadequate activation of this signaling pathway. The last explanation appears to be the most likely. The EGFP coexpression cassette revealed that virtually all the cardiomyocytes were transduced by Ad.BD110 at an MOI of 10 pfu/cell, consistent with previous reports.17 In addition, the substantially greater benefit conferred by Ad.myr-Akt-HA at high MOI provides evidence that further activation of this pathway alone is sufficient to protect hypoxic cardiomyocytes from apoptosis. It remains unclear why infection with Ad.BD110 killed even normoxic cardiomyocytes at high MOI; however, it may not be surprising that cells do not tolerate massive overexpression of this proximal kinase critical to so many fundamental cellular processes. Such observations may help guide future approaches to targeting these pathways in vivo and suggest that manipulation of Akt may ultimately prove to be a more robust strategy.
IGF-1 has been documented to inhibit caspase activity in cardiomyocytes.18 Akt can inhibit caspase-mediated cell death through multiple mechanisms,6 7 including release of antiapoptotic Bcl-family members.5 Of note, adenoviral overexpression of Bcl-2 in cardiomyocytes is itself sufficient to prevent p53-mediated apoptosis.19 We hypothesized that the survival benefit we observed in cardiomyocytes after expression of activated Akt or PI 3-kinase was probably mediated through caspase inhibition and tested the effects of a direct caspase inhibitor, z-VAD.fmk, in this model. In hypoxic cardiomyocytes, z-VAD.fmk blocked apoptosis to an extent comparable to the maximal benefit achieved through adenoviral activation of the PI 3-kinase/Akt signaling pathway. These results suggest that caspase inhibition could account for the benefits seen with adenoviral gene transfer of activated PI 3-kinase or Akt but do not establish a direct connection between these pathways in cardiomyocytes. It also remains to be seen whether the importance of these pathways will be conserved with other proapoptotic stimuli as well as in other in vitro and in vivo models.
Critical unanswered questions include the fate and functional capacity of cardiomyocytes in which apoptosis has been inhibited through activation of these signaling molecules. It is possible that these cells will simply die through another mechanism, such as necrosis or oncosis. Even if such cardiomyocytes survive, they may not function normally. Many pathways may contribute to hypoxia-induced myocyte dysfunction, and thus, inhibition of apoptosis could increase survival without improving the function of the surviving cells. Remarkably, the majority of cardiomyocytes transduced with BD110 at an MOI of 10 pfu/cell or myr-Akt at higher MOI continued to contract spontaneously and vigorously even after 24 hours of hypoxia, whereas virtually all cells transduced with the control virus stopped beating after hypoxia (data not shown). Rigorously defining the functional implications of specific apoptosis-related signaling pathways will be an important focus of future studies that should be facilitated by the gene transfer approach illustrated in the present study.
The present data are consistent with previous studies documenting the ability of IGF-1 to block apoptosis in many cell types, including cardiomyocytes,18 and to mediate beneficial effects in animal models of myocardial ischemia, whether delivered through peptide injection2 or transgenically overexpressed in the heart.20 Although it is tempting to speculate that activation of PI 3-kinase and Akt may play a role in the IGF-1–mediated benefits seen in these animal models,2 20 IGF-1 has systemic effects that could confound such studies. The recombinant vectors described in this report should provide useful tools for examining the relative contribution of local activation of PI 3-kinase and Akt to the observed benefits of IGF-1 in vivo. Understanding the role of specific pathways in cardiomyocyte apoptosis may help identify targets and novel therapeutic strategies for intervention in conditions such as myocardial infarction and heart failure.
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Acknowledgments |
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This work was supported in part by grants from the NIH (HL-50361 and HL-57623 to Dr Hajjar; HL-59521 and HL-61557 to Dr Rosenzweig). Dr Rosenzweig is an Established Investigator of the American Heart Association. Dr Matsui is supported by an American Heart Association Fellowship. The authors thank Drs Thomas Force, Kazuyoshi Yonezawa, and Kenta Hara for their insightful suggestions. The technical assistance of Drs Zhaobin Kang and Quifen Qui is greatly appreciated, as is Paula Kaltofen’s help with manuscript preparation.
Received March 26, 1999; revision received June 29, 1999; accepted July 9, 1999.
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L. G. Melo, A. S. Pachori, D. Kong, M. Gnecchi, K. Wang, R. E. Pratt, and V. J. Dzau Molecular and Cell-Based Therapies for Protection, Rescue, and Repair of Ischemic Myocardium: Reasons for Cautious Optimism Circulation, May 25, 2004; 109(20): 2386 - 2393. [Full Text] [PDF]
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D. J Hausenloy and D. M Yellon New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway Cardiovasc Res, February 15, 2004; 61(3): 448 - 460. [Abstract] [Full Text] [PDF]
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H. A. Baba, J. Stypmann, F. Grabellus, P. Kirchhof, A. Sokoll, M. Schafers, A. Takeda, M. J. Wilhelm, H. H. Scheld, N. Takeda, et al. Dynamic regulation of MEK/Erks and Akt/GSK-3{beta} in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism Cardiovasc Res, August 1, 2003; 59(2): 390 - 399. [Abstract] [Full Text] [PDF]
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M. N. Sack and D. M. Yellon Insulin therapy as an adjunct toreperfusion after acute coronary ischemia: A proposed direct myocardial cell survival effect independent of metabolic modulation J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1404 - 1407. [Abstract] [Full Text] [PDF]
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E. J. Su, C. L. Cioffi, S. Stefansson, N. Mittereder, M. Garay, D. Hreniuk, and G. Liau Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1429 - H1440. [Abstract] [Full Text] [PDF]
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T. Krieg, M. Landsberger, M. F. Alexeyev, S. B. Felix, M. V. Cohen, and J. M. Downey Activation of Akt is essential for acetylcholine to trigger generation of oxygen free radicals Cardiovasc Res, April 1, 2003; 58(1): 196 - 202. [Abstract] [Full Text] [PDF]
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T. Krieg, Q. Qin, E. C. McIntosh, M. V. Cohen, and J. M. Downey ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2322 - H2330. [Abstract] [Full Text] [PDF]
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J. Wechsler, Y.-H. Choi, J. Krall, F. Ahmad, V. C. Manganiello, and M. A. Movsesian Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3A in Cardiac Myocytes J. Biol. Chem., October 4, 2002; 277(41): 38072 - 38078. [Abstract] [Full Text] [PDF]
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T. Tokudome, T. Horio, F. Yoshihara, S.-i. Suga, Y. Kawano, M. Kohno, and K. Kangawa Adrenomedullin Inhibits Doxorubicin-Induced Cultured Rat Cardiac Myocyte Apoptosis via a cAMP-Dependent Mechanism Endocrinology, September 1, 2002; 143(9): 3515 - 3521. [Abstract] [Full Text] [PDF]
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W. Chao, Y. Shen, L. Li, and A. Rosenzweig Importance of FADD Signaling in Serum Deprivation- and Hypoxia-induced Cardiomyocyte Apoptosis J. Biol. Chem., August 23, 2002; 277(35): 31639 - 31645. [Abstract] [Full Text] [PDF]
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M. T. Crow Hypoxia, BNip3 Proteins, and the Mitochondrial Death Pathway in Cardiomyocytes Circ. Res., August 9, 2002; 91(3): 183 - 185. [Full Text] [PDF]
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T. Matsui, L. Li, J. C. Wu, S. A. Cook, T. Nagoshi, M. H. Picard, R. Liao, and A. Rosenzweig Phenotypic Spectrum Caused by Transgenic Overexpression of Activated Akt in the Heart J. Biol. Chem., June 14, 2002; 277(25): 22896 - 22901. [Abstract] [Full Text] [PDF]
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S. E. Hardt and J. Sadoshima Glycogen Synthase Kinase-3{beta}: A Novel Regulator of Cardiac Hypertrophy and Development Circ. Res., May 31, 2002; 90(10): 1055 - 1063. [Abstract] [Full Text] [PDF]
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F. B. Mehrhof, F. U. Muller, M. W. Bergmann, P. Li, Y. Wang, W. Schmitz, R. Dietz, and R. von Harsdorf In Cardiomyocyte Hypoxia, Insulin-Like Growth Factor-I-Induced Antiapoptotic Signaling Requires Phosphatidylinositol-3-OH-Kinase-Dependent and Mitogen-Activated Protein Kinase-Dependent Activation of the Transcription Factor cAMP Response Element-Binding Protein Circulation, October 23, 2001; 104(17): 2088 - 2094. [Abstract] [Full Text] [PDF]
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T. Matsui, J. Tao, F. del Monte, K.-H. Lee, L. Li, M. Picard, T. L. Force, T. F. Franke, R. J. Hajjar, and A. Rosenzweig Akt Activation Preserves Cardiac Function and Prevents Injury After Transient Cardiac Ischemia In Vivo Circulation, July 17, 2001; 104(3): 330 - 335. [Abstract] [Full Text] [PDF]
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F. del Monte, R. J. Hajjar, S. E. Harding, and G. Inesi Overwhelming Evidence of the Beneficial Effects of SERCA Gene Transfer in Heart Failure Response Circ. Res., June 8, 2001; 88 (11): e66 - e67. [Full Text] [PDF]
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K. Yamashita, J. Kajstura, D. J. Discher, B. J. Wasserlauf, N. H. Bishopric, P. Anversa, and K. A. Webster Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1 Circ. Res., March 30, 2001; 88(6): 609 - 614. [Abstract] [Full Text] [PDF]
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A. Chesley, M. S. Lundberg, T. Asai, R.-P. Xiao, S. Ohtani, E. G. Lakatta, and M. T. Crow The {beta}2-Adrenergic Receptor Delivers an Antiapoptotic Signal to Cardiac Myocytes Through Gi-Dependent Coupling to Phosphatidylinositol 3'-Kinase Circ. Res., December 8, 2000; 87(12): 1172 - 1179. [Abstract] [Full Text] [PDF]
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R. J. Hajjar, F. del Monte, T. Matsui, and A. Rosenzweig Prospects for Gene Therapy for Heart Failure Circ. Res., March 31, 2000; 86(6): 616 - 621. [Abstract] [Full Text] [PDF]
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S. Fukumoto, C.-M. Hsieh, K. Maemura, M. D. Layne, S.-F. Yet, K.-H. Lee, T. Matsui, A. Rosenzweig, W. G. Taylor, J. S. Rubin, et al. Akt Participation in the Wnt Signaling Pathway through Dishevelled J. Biol. Chem., May 11, 2001; 276(20): 17479 - 17483. [Abstract] [Full Text] [PDF]
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W. Wu, W.-L. Lee, Y. Y. Wu, D. Chen, T.-J. Liu, A. Jang, P. M. Sharma, and P. H. Wang Expression of Constitutively Active Phosphatidylinositol 3-Kinase Inhibits Activation of Caspase 3 and Apoptosis of Cardiac Muscle Cells J. Biol. Chem., December 15, 2000; 275(51): 40113 - 40119. [Abstract] [Full Text] [PDF]
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D. Camper-Kirby, S. Welch, A. Walker, I. Shiraishi, K. D. R. Setchell, E. Schaefer, J. Kajstura, P. Anversa, and M. A. Sussman Myocardial Akt Activation and Gender : Increased Nuclear Activity in Females Versus Males Circ. Res., May 25, 2001; 88(10): 1020 - 1027. [Abstract] [Full Text] [PDF]
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