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1 modulates NOS expression and phosphorylation
of Akt/PKB in rat myocytes exposed to hypoxia-reoxygenation
1 Department of Medicine and Physiology, University of Arkansas and Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205-7199; and 2 Department of Forensic Medicine, University of Uppsala, Uppsala, Sweden S-752-37
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial hypoxia-reoxygenation (H-R) is associated with
upregulation of inducible nitric oxide synthase (iNOS), decrease in
endothelial NOS (eNOS), and increase in protein kinase B (PKB). Previous work also shows that transforming growth
factor-
1 (TGF-1) can attenuate myocardial
injury induced by H-R. We examined the modulation of NOS and PKB
expression in response to H-R by TGF- 1. Myocytes from
Sprague-Dawley rat hearts were cultured and exposed to hypoxia (95%
N2-5% CO2, PO2 ~30
mmHg) for 24 h and reoxygenation (95% air-5% CO2)
for 3 h. Myocytes were then examined for lactate dehydrogenase
(LDH) release, iNOS activity (conversion of
L-[3H]arginine to
L-[3H]citrulline), iNOS and eNOS expression,
and PKB phosphorylation. H-R alone resulted in myocyte injury,
upregulation of iNOS activity and expression, decrease in eNOS
expression, and increase in PKB phosphorylation (all P < 0.05 vs. cells cultured in normoxic conditions). Treatment of
myocytes with TGF-1 (1 ng/ml) resulted in a reduction in
LDH release, attenuation of the alterations in NOS expression (both
iNOS and eNOS), and PKB phosphorylation in response to H-R (all
P < 0.05 vs. H-R alone). These observations suggest
that TGF-1 decreases H-R injury and attenuates
alterations in NOS and PKB phosphorylation in myocytes exposed to H-R.
nitric oxide; protein kinase B; transforming growth factor; apoptosis; endothelium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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NITRIC OXIDE (NO) plays a critical role in modulating cardiac function during ischemia. NO can be synthesized in cardiac tissues by all three isoforms of NO synthase (NOS), neuronal NOS, endothelial NOS (eNOS), and inducible NOS (iNOS) (11, 38). iNOS and eNOS are thought to participate in several cardiovascular disease processes, such as hypertension, atherosclerosis, heart failure, myocardial infarction, and myocardial hypoxia-reoxygenation (H-R) injury (3, 10, 39-42). A body of evidence suggests that eNOS exerts a protective effect on myocardium against H-R injury (13, 36). However, the precise role of iNOS on myocardium subjected to H-R remains unclear (16, 19, 40-42).
Phosphatidylinositol (PI) 3-kinase and its downstream
serine-threonine kinase, Akt/protein kinase B (Akt/PKB) are important signal transduction pathways involved in many cellular processes, including proliferation, apoptosis, and survival (8,
35). Akt/PKB can be activated by a variety of growth factors,
such as platelet-derived growth factor, epidermal growth factor,
insulin, thrombin, and nerve growth factor (8). Mockridge
et al. (29) showed that Akt/PKB is activated in myocytes
during H-R. Another study (4) reported that activation of
Akt/PKB inhibits transforming growth factor-1
(TGF-1)-induced apoptosis in liver cells.
TGF-1 is thought to be a multifunctional polypeptide
that influences cardiac development and function (30).
Data from several laboratories, including ours, show that H-R causes an
increase in latent TGF-1 levels, but a decrease in its
active form (14, 28). Supplementation with exogenous
TGF-1 can protect the heart from H-R injury (21,
28, 43) and subsequent autoinduction of TGF-1
(22). Krymskaya et al. (18) found that
TGF-1 can modulate epidermal growth factor-induced
Akt/PKB activation in human airway smooth muscle cells. However, the
relationship between the protective effect of TGF-1
against the adverse effects of H-R in relationship to the expression of
NOS and Akt/PKB remains unclear. The present study was designed to
study this relationship.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocyte isolation and culture. Calcium-tolerant myocytes were obtained by using a combination of the perfusion technique of Claycomb and Palazzo (6) with a modification of the procedure (26), as detailed earlier (43). All procedures were carried out under aseptic conditions. Adult male Sprague-Dawley rats weighing 200-250 g were given heparin (1,000 U/kg ip) and anesthetized with pentobarbital sodium (60 mg/kg). The thorax was opened, and the heart was removed and placed into ice-cold Ca2+-free Krebs-Henseleit (K-H) buffer perfusion medium of (in mM) 118 NaCl, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4, 25 NaHCO3, and 11 glucose, pH 7.4. Within 1 min, the heart was transferred to a perfusion apparatus and perfused via the aorta with oxygen-saturated (95% O2-5% CO2) Ca2+-free K-H buffer at 37°C at a rate of 5 to 6 ml/min for 5 min. Then the heart was perfused with 1 mg/ml of crude collagenase type XI (Sigma) in the same medium for 15 to 20 min to rinse out the intervascular space.
After perfusion, the heart was removed, and the atria and large vessels were dissected off. Ventricles were minced into small pieces and then shaken in 10 ml of perfusion medium containing 2% bovine serum albumin at 37°C for 5 min. The released cells were collected and centrifuged at 10 g for 5 min. The pellet of cells was then washed repeatedly. The cells were resuspended in cell culture medium containing 5% fetal bovine serum and antibiotics. With this method, ~70-80% of cardiomyocytes were found to be rod shaped. Cells from each rat heart were divided into 10-cm dishes containing 10 ml of Dulbecco's modified Eagle's medium composed of 10% fetal bovine serum, 100 U/ml penicillin, and 0.1 mg/ml streptomycin (about 106 cells in each dish) and were cultured under 95% air-5% CO2 at 37°C. Culture medium was changed every other day. Myocytes were divided into four groups: 1) control group, myocytes were incubated in 95% air-5% CO2; 2) H-R group, myocytes were exposed to 24 h of hypoxia (95% N2-5% CO2, PO2 ~30 mmHg), followed by 3 h of reoxygenation (95% air-5% CO2); 3) TGF-1 plus H-R group,
myocytes were incubated with human recombinant TGF-1 (1 ng/ml) (Calbiochem) followed by exposure to H-R; and 4)
TGF-1 plus normoxia group, myocytes were incubated with
TGF-1 (1 ng/ml) in 95% air-5% CO2.
Supernatant of myocytes was then collected for determination of lactate
dehydrogenase (LDH). Myocytes were harvested for examination of iNOS
activity, iNOS and eNOS expression, as well as Akt/PKB expression and
its phosphorylation.
Determination of LDH in culture medium. A spectrophotometric method based on the oxidation of lactate (Sigma) was used to measure LDH release. LDH activity was expressed as units per milliliters of medium (24).
Determination of iNOS activity in myocytes.
iNOS activity in cultured myocytes was measured by monitoring the
conversion of L-[3H]arginine into
L-[3H]citrulline (5). Freshly
harvested myocytes were suspended and lysed. The lysate was centrifuged
at 10,000 rpm for 20 min. Lysate supernatant (100 µl) and
L-[3H]arginine (100 nM) were mixed with
reaction buffer containing 50 mM HEPES (pH 7.4), 1.5 mM
-nicotinamide adenine dinucleotide phosphate, 1 mM dithiothreitol, 1 mM EDTA, 1 mM MgCl2, 2.5 µM flavin adenine dinucleotide,
and 1 µM tetrahydrobiopterin and incubated for 30 min at 37°C. The
reaction was terminated with stop buffer 20 mM HEPES and 2 mM EDTA (pH
5.5), and the mixture was applied to Dowex AG50W-X8 (Na+
form) columns and eluted with 4 ml of distilled water.
L-[3H]citrulline was counted and iNOS
activity was expressed as nanometer per milligram protein.
Determination of NOS protein in myocytes. Myocyte lysates from each experiment (80 µg/lane) were separated by 6% SDS-PAGE using a Bio-Rad miniprotean cell and transferred to nitrocellulose membrane (Amersham). After incubation in blocking solution (5% nonfat milk, Sigma), membranes were incubated with 1:1,000 dilution primary antibody (polycolonal antibody to iNOS or eNOS, Santa Cruz Biotechnology) overnight at 4°C. Membranes were washed and incubated with 1:1,000 dilution second antibody (Amersham) for 1 h. The membranes were detected with the enhanced chemiluminescence system, as described previously (23, 24).
Determination of NOS mRNA in myocytes.
The methodology for NOS mRNA determination has been described earlier
(23, 24). The primer pairs specific to iNOS were forward
5'-GATAATAACCTGAAGCCCG-3' and reverse 5'-GCCCTTTTTTGCTCCATAGG-3'. The
eNOS primers were forward 5'-TACGGAGCAGCAAATCCAC-3' and reverse 5'-GATCAAAGGACTGCACCTG-3'. The amplified samples were visualized on
1.0% agarose gel using ethidium bromide. A primer pair of rat -actin was used as the control. Relative intensity of bands of interest were analyzed by scanner NSF-300G (Microtek).
Immunoprecipitation and detection of Akt/PKB and its phosphorylation. The methodology for immunoprecipitation and Western analysis has been described earlier (23, 24). The primary polycolonal antibodies to Akt/PKB and phospho-Akt/PKB were obtained from New England Biolabs (dilution 1:1,000). The secondary antibody was from Amersham.
Data analysis. Data are presented as means ± SE. Statistical significance was determined in multiple comparisons among independent groups of data in which ANOVA and the Student-Newman-Keuls test indicated the presence of significant differences. A P value of <0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of TGF-1 on myocardial injury induced by
hypoxia-reoxygenation.
H-R caused a marked increase in LDH release in the supernatants of
myocytes, indicating myocyte injury (P < 0.05 vs.
control group, n = 5). Treatment of cultured myocytes
with TGF-1 before H-R attenuated LDH release in response
to H-R (P < 0.05 vs. H-R group, n = 5). Notably, there was no effect of TGF-1 on LDH release in the medium of myocytes cultured under normoxic conditions (Fig. 1).
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Effect of TGF-1 on iNOS activity in myocytes.
As shown in Fig. 2, iNOS activity was
markedly upregulated in cultured myocytes exposed to H-R
(P < 0.05 vs. control). Treatment of myocytes with
TGF-1 reduced this enhanced iNOS activity during H-R
(P < 0.05 vs. alone). Exogenous TGF-1
did not affect iNOS activity in myocytes cultured under normoxic
conditions.
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Effect of TGF-1 on NOS expression in
myocytes.
As shown in Fig. 3, iNOS
expression (protein and mRNA) was increased, whereas eNOS expression
(protein and mRNA) was decreased in cultured myocytes exposed to H-R
(P < 0.05 vs. control). Treatment of myocytes with
exogenous TGF-1 attenuated the increase in iNOS expression and the decrease in eNOS expression during H-R (both P < 0.05 vs. H-R alone). TGF-1 did not
affect iNOS or eNOS expression in myocytes cultured under normoxic
conditions.
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Effect of TGF-1 on Akt/PKB phosphorylation in
myocytes.
H-R did not affect the Akt/PKB protein in cultured myocytes; however,
the phospho-Akt/PKB level increased during H-R (P < 0.05 vs. control group). Treatment with TGF-1 reduced
the increased levels of phospho-Akt/PKB during H-R (P < 0.05 vs. H-R alone) (Fig. 4). Note
that TGF-1 did not affect Akt/PKB or phospho-Akt/PKB levels in myocytes cultured under normoxic conditions.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study shows that H-R significantly injures cultured
myocytes, as indicated by LDH release into the medium, and the cell
injury is associated with an upregulation of iNOS activity and
expression, downregulation of eNOS expression, and enhancement of
Akt/PKB phosphorylation. Treatment with TGF-1 attenuates
myocyte injury and blocks the increase in iNOS activity and expression and PKB phosphorylation, as well as the decrease in eNOS expression.
Many studies have demonstrated that total NO production and iNOS
expression are increased in myocytes incubated with cytokines, such as
interleukin-1 (IL-1), tumor necrosis factor-
(TNF-), interferon-
(IFN-), and lipopolysaccharide (27, 33).
Other studies have shown that H-R is associated with an increase in iNOS expression (34, 42) and a decrease in eNOS expression (13) in myocytes. Results of the present study are in
accordance with the results of these studies (13, 34, 42).
Several studies have confirmed the beneficial effect of eNOS
upregulation on myocardial tissues exposed to H-R (13,
36), but the role of overexpression of iNOS during H-R continues
to be debated. For example, some studies have shown that inhibition of
iNOS expression can block ischemic injury in the cardiac and
renal tissues (25, 40-42) because large amounts of NO
released as a result of iNOS overexpression can directly cause
myocardial injury (42). On the other hand, a recent study
in an iNOS-knockout mice model (16) showed protection of
myocardium from the adverse effects of H-R. These disparate results may
relate to the differences in NO production in the myocytes, because
moderate amounts of NO may be protective, and excessive production of
NO may contribute to cardiac injury (9, 14, 31, 40).
A previous study from our laboratory (28) suggested that
latent TGF-1 increases and active TGF-1
decreases during myocardial ischemia-reperfusion. In addition,
we and others (20, 21, 28, 43, 44) found that exogenous
TGF-1 can attenuate H-R injury to the myocardium.
TGF-1 has been reported to alleviate myocardial injury
by inhibition of TNF- release, improvement in endothelium-dependent
relaxation of coronary arteries, and prevention of superoxide anion
generation (20). TGF-1 can also inhibit the
activation of iNOS induced by cytokines, which are expressed in the
ischemic heart (32). Szabolcs et al.
(37) found that myocardial injury, in particular,
apoptosis, is closely linked with the upregulation of iNOS
expression in macrophages and myocytes. Others have shown that myocyte
apoptosis in response to IL-1 and IFN- is mediated via
iNOS induction, and both nonselective and selective NOS inhibitors
prevent myocyte injury induced by cytokines (1).
The present study shows that small amounts of exogenous
TGF-1 can protect myocytes from the injurious effects of
H-R, with simultaneous inhibition of enhanced iNOS activity and
expression. Importantly, the present study for the first time showed
that exogenous TGF-1 can also ameliorate the decrease in
eNOS expression in myocytes exposed to H-R. These observations collectively indicate that the modulation of NOS expression may be an
important mechanism of the cardioprotective effect of
TGF-1 against the injurious effects of H-R.
Growing evidence suggests that Akt/PKB activation plays an important
role in a variety of cellular processes (8, 35). Activation of receptor tyrosine kinases and G protein-coupled receptors
and stimulation of cells by mechanical and cytokines can activate
Akt/PKB (7, 8). However, the significance of Akt/PKB
phosphorylation and activation in the myocardium subjected to H-R is
not clear. Mockridge et al. (29) have recently reported that ischemia-reperfusion, but not ischemia alone,
induces Akt/PKB phosphorylation on both S473 and T308 residues in
neonatal rat cardiomyocytes. Similar observations have been made in the
ischemic brain (17). The present study showed that
H-R increases Akt/PKB phosphorylation on S473 residue without effecting
protein expression in cultured rat myocytes. Treatment of myocytes with
TGF-1 blocked this increase in Akt/PKB phosphorylation
and simultaneously protected myocytes against the adverse effects of
H-R, suggesting that reduction of Akt/PKB phosphorylation may be an
important mechanism of cardioprotection by TGF-1.
Experimental studies have demonstrated that activation of Akt/PKB is an
important signaling pathway in the expression of eNOS (12). Another study has suggested that PI3-kinase and
Akt/PKB signaling is required for TGF-1-induced
transcriptional responses and cell migration (2).
Krymskaya et al. (18) found that TGF-1 can
modulate epidermal growth factor-induced Akt/PKB activation in human
airway smooth muscle cells. The present study showed that
TGF-1 simultaneously blocks increase in iNOS expression (and activity) as well as Akt/PKB phosphorylation in myocytes exposed
to H-R. Because there is no specific promoter for PI3-kinase and PKB,
the relationship between Akt/PKB and iNOS expression cannot be
precisely established from this study. However, this study strongly
suggests that modulation of iNOS expression by TGF-1 is
mediated via the Akt/PKB pathway. We believe that the increased NOS
activity in the supernatants of myocytes exposed to H-R was a
reflection of markedly increased iNOS expression because the buffer
used for culture of myocytes was devoid of Ca2+ and calmodulin.
In summary, the present study shows that TGF-1 modulates
enhanced iNOS expression and Akt/PKB phosphorylation in myocytes exposed to H-R. These observations provide a novel insight into the
mechanism of the protective effect of TGF-1 on myocytes
against H-R injury.
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ACKNOWLEDGEMENTS |
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This study was supported by a Merit Review grant from the Department of Veterans Affairs, a contract with the Department of Defense, and funds from the Swedish Medical Research Council, Wrenette Worthen Williamson Cardiology Research Endowment, and Howard and Elsie Stebbins Endowed Chair in Cardiology.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. L. Mehta, Division of Cardiovascular Medicine, Univ. of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 532, Little Rock, AR 72205-7199 (E-mail: MehtaJL{at}UAMS.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 December 2000; accepted in final form 11 May 2001.
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ABSTRACT
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RESULTS
DISCUSSION
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