(Hypertension. 2000;35:1191.)
© 2000 American Heart Association, Inc.
Cooper Lecture |
Cardiotrophin-1 Increases Angiotensinogen mRNA in Rat Cardiac Myocytes Through STAT3
An Autocrine Loop for Hypertrophy
From the Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine (J.F., D.E.D., G.W.B., K.M.B.), Temple, Tex; and the Henry Hood Research Program, Sigfried and Janet Weis Center for Research, Pennsylvania State University College of Medicine (R.A.H., V.K., N.S.), Danville, Penn.
Correspondence to Kenneth M. Baker, MD, Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, 1901 S 1st St, Bldg 162, Temple, TX 76504. E-mail kbaker{at}medicine.tamu.edu
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Abstract—Cardiotrophin-1, an interleukin-6–related cytokine, stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and induces cardiac myocyte hypertrophy. In this study, we demonstrate that cardiotrophin-1 induces cardiac myocyte hypertrophy in part by upregulation of a local renin-angiotensin system through the JAK/STAT pathway. We found that cardiotrophin-1 increased angiotensinogen mRNA expression in cardiac myocytes via STAT3 activation. Tyrosine phosphorylation of STAT3 by cardiotrophin-1 treatment resulted in STAT3 homodimer binding to the St-domain in the angiotensinogen gene promoter, which lead to promoter activation in a transient transfection assay. Cardiotrophin-1–induced STAT3 tyrosine phosphorylation and binding to the St-domain were suppressed by AG490, a specific JAK2 inhibitor, which also attenuated cardiotrophin-1–stimulated angiotensinogen promoter activity. Cardiotrophin-1 did not activate the angiotensinogen gene promoter that contained a substitution mutation within the St-domain. Finally, losartan, an angiotensin II type 1 receptor antagonist, significantly attenuated cardiotrophin-1–induced hypertrophy of neonatal rat cardiac myocytes. Angiotensin II is known to induce cardiac myocyte hypertrophy by activating the G-protein–coupled angiotensin II type 1 receptor. Our results suggest that upregulation of angiotensinogen and angiotensin II production contribute to cardiotrophin-1–induced cardiac myocyte hypertrophy and emphasize an important interaction between G-protein–coupled and cytokine receptors.
Key Words: angiotensinogen • gene expression • promoter regions • motifs • Janus kinases • STAT pathway • cardiac myocyte
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Introduction |
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Cardiotrophin-1 (CT-1), a newly isolated member of the interleukin (IL)-6–related cytokine family, which includes IL-6 and leukemia inhibitory factor (LIF), is a potent inducer of cardiac myocyte hypertrophy and gene expression.1 2 CT-1, via coupling through the LIF receptor and gp130, has been shown to activate a number of signaling pathways in cardiac myocytes, including mitogen-activated protein kinases and the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway.3 4 On tyrosine phosphorylation by JAK, STAT proteins undergo dimerization, translocate to the nucleus, and activate expression of target genes.5 Recent reports implicate the JAK/STAT pathway in cardiac hypertrophy: 2 potent hypertrophic stimuli, acute pressure overload and mechanical stretch, activate the JAK/STAT pathway in cardiac myocytes,6 7 8 and nuclear extracts from hypertrophied hearts of genetically hypertensive SHR rats exhibit enhanced STAT binding activity compared with extracts of aged-matched normotensive Wistar-Kyoto rats.9 Moreover, LIF was shown to induce cardiac myocyte hypertrophy through the JAK/STAT pathway.10 11 LIF-induced cardiac myocyte hypertrophy and expression of c-fos and atrial natriuretic factor mRNA were amplified by STAT3 overexpression and attenuated by a STAT3-dominant negative mutant.12 However, the process by which the JAK/STAT signaling pathway couples to hypertrophic growth in cardiac myocytes has not been defined.
In the present study, we hypothesized that CT-1 activation of the JAK/STAT pathway couples to hypertrophic growth of cardiac myocytes through upregulation of angiotensinogen (Ao) gene expression. This hypothesis is based on the recent observation that the Ao gene promoter is activated by STAT3 and STAT6 proteins.9 The activated STAT proteins bind to a motif, denoted the St-domain, in the Ao gene promoter, and STAT3 and STAT6 proteins have recently been implicated in angiotensin (Ang) II–induced Ao gene expression in neonatal rat cardiac myocytes.9 Local production of Ang II could thus contribute to CT-1–induced hypertrophic growth of cardiac myocytes. The feasibility of this hypothesis is supported by the observation that autocrine release of Ang II is involved in stretch-induced JAK/STAT activation and hypertrophy of cardiac myocytes.7 13 14
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Methods |
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Materials
Reagents for tissue culture were obtained from Gibco BRL. STAT antibodies and protein A/G agarose were from Santa Cruz Biotechnology. STAT1 (phosphotyrosine [p-Tyr]701) and STAT3 (p-Tyr705) phosphospecific antibodies were from Quality Controlled Biochemicals. Antiphosphotyrosine (4G10) and STAT5 (p-Tyr694) phosphospecific antibodies were from Upstate Biotechnology. Human CT-1 was from PeproTech (Norwood, Mass), AG490 was from BioMol, and losartan and PD123319 were from Sigma Chemical Co. [3H]-Leucine, [
-32P]-ATP, chemiluminescence reagents, and
nitrocellulose membranes were from NEN Life Science. Poly(dI-dC) was
from Pharmacia Biotech. T4 polynucleotide kinase and
reporter lysis buffer were from Promega. RNAzol B was purchased from
Tel Test. Effectene was from Qiagen. Plasmids that contained a
wild-type or a mutant St-domain of the Ao gene promoter, ligated to a
luciferase reporter gene, were a gift of Drs Eduardo M. Mascareno and
M.A.Q. Siddiqui (State University of New York Health Science Center
at Brooklyn).
Cardiac Myocyte Isolation
Ventricular cardiac myocytes were isolated from
neonatal Sprague-Dawley rat hearts as described15 and
plated at 0.35x103
cells/mm2. After 24 hours, the medium was changed
to serum-free DMEM/F-12 with 100 µmol/L ascorbic acid and 68 U/L
insulin. Twenty-four hours before an experiment, cells were given the
same medium without ascorbic acid or insulin.
Quantification of mRNA, Reporter Plasmids, and Transient
Transfection Assay
Cardiac myocytes were treated for 4 hours with CT-1 (1 nmol/L),
and RNA was extracted with RNAzol B. Ao, renin,
angiotensin II type 1 (AT1) receptor,
and elongation factor-1
mRNA were quantified by multiplex reverse
transcription–polymerase chain reaction, as described.16
Details of plasmids containing a normal (CTTCCTGGAAG) or
mutated (CGACCTGGAAG) St-domain of the rat Ao promoter (base
positions +47 to -175 of the entire gene) may be found
elsewhere.9 Transfection of cardiac myocytes with
plasmids was performed with Effectene, according to the
manufacturer’s instructions. Cell lysates were prepared, and
luciferase activity was measured with a Micro Lumat Plus luminometer
(EG&G Berthold), with commercially available reagents (Promega).
Immunoprecipitation and Immunoblotting
Immunoprecipitation of STAT6 was performed with 500 µg of cell
lysate.17 To measure STAT protein tyrosine
phosphorylation, immunoprecipitated samples (for STAT6)
or 5 µg of cell lysate (for STATs 1, 3, and 5) were mixed with 4x
sample buffer (5% SDS, 500 mmol/L Tris-HCl [pH 7.5], 50%
glycerol, and 0.25% bromophenol blue) and boiled 5 minutes. Samples
were subjected to 8% SDS-PAGE, and separated proteins were transferred
to nitrocellulose membranes, which were incubated with a pTYR-specific
STAT antibody (STATs 1, 3, and 5) or an anti-pTYR antibody (STAT6).
After incubation with secondary antibody, immunoreactive bands were
visualized by enhanced chemiluminescence.
Preparation of Nuclear Extracts, and Electrophoretic Mobility Shift
and Supershift Assays
Previously described methods were used to prepare nuclear
extracts and perform the electrophoretic mobility shift
assay.17 Sequences and end labeling of
oligonucleotides have been
described.7 9 17 For supershift assays, STAT antibodies (1
µg) were incubated 30 minutes with DNA-protein complexes at 4°C.
Reactions were analyzed by native 4% PAGE.7 Gels
were dried and visualized by autoradiography or
phosphorimage analysis.7
Measurement of Cardiac Myocyte Hypertrophy
Cardiac myocyte hypertrophy was evaluated by
[3H-leucine incorporation (index of protein
synthesis) and by total cellular protein normalized to DNA (index of
cell size).15 Cardiac myocytes were labeled with 1.0
µCi/mL [3H]-leucine for 4 hours after 20
hours of treatment with CT-1 (1 nmol/L). Cells were pretreated with
losartan (1 µmol/L) or PD123319 (10 µmol/L) for
30 minutes before CT-1 treatment. Protein and DNA contents were
measured as described.15 In these experiments, cells were
treated with CT-1, in the presence or absence of losartan
(1 µmol/L), for 24, 48, or 72 hours.
Statistics
Results were expressed as mean±SEM. Differences among groups
were assessed by 1-way ANOVA followed by the Dunnet multiple comparison
test. P
0.05 was considered statistically
significant.
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Results |
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CT-1 Increases Ao mRNA Levels and Promoter Activity
CT-1 (1 nmol/L) increased Ao mRNA at 4 hours by 220% (Figure 1a and 1c). Levels of mRNA for renin and the AT1 receptor were not increased (Figure 1a through 1c). To determine whether CT-1 increased Ao gene promoter activity through the St-domain, cardiac myocytes were transiently transfected with a plasmid that contain the St-domain (STANGLuc) of the Ao gene promoter linked to a luciferase reporter gene. Stimulation with CT-1 (1 nmol/L) for 1, 2, or 4 hours increased luciferase activity by 127.4%, 85.1%, and 33.6%, respectively (Figure 2a). CT-1 stimulation did not increase luciferase activity in cardiac myocytes transfected with a plasmid that contained a mutant St-domain (MSTANGLuc, Figure 2a). Pretreatment of cells for 30 minutes with AG490, a specific JAK2 inhibitor,7 inhibited CT-1–stimulation of promoter activity of STANGLuc in a concentration-dependent manner (Figure 2b).
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CT-1 Induces Tyrosine Phosphorylation of STAT
Proteins in Cardiac Myocytes
The time course for CT-1–induced tyrosine
phosphorylation of various STAT proteins was determined
by Western blot analysis (Figure 3). As reported by others,3
we observed that CT-1 induced tyrosine phosphorylation
of STAT3 (Figure 3b). In addition, STAT1 and STAT5 were tyrosine
phosphorylated (Figures 3a and 3c). Detectable
phosphorylation of STATs 1, 3, and 5 occurred in 2 to 5
minutes and was maximal at 10 to 15 minutes. CT-1 did not induce STAT6
tyrosine phosphorylation (Figure 3d).
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CT-1 Enhances STAT3 Binding Activity to the St-Domain of
Cardiac Myocytes
Because CT-1 induced the tyrosine phosphorylation
of STATs 1, 3, and 5, binding activity of these STAT proteins to the
St-domain of the Ao promoter was evaluated. Nuclear extracts from
CT-1–treated cardiac myocytes exhibited enhanced binding to the
St-domain in a time- (Figure 4a) and
concentration- (Figure 4b) dependent manner. Specificity of
binding to the St-domain was confirmed with a mutant probe and by
adding excess a wild-type or a mutant St-domain
oligonucleotide (Figure 4c). Supershift assay
was used to identify the STAT proteins in nuclear extracts that
exhibited enhanced binding to the St-domain (Figure 4d). Only
STAT3 homodimer exhibited enhanced binding to the St-domain, and
thus CT-1–induced tyrosine phosphoryation of STAT3 was further
characterized. As shown in Figure 4f, CT-1 induced STAT3
tyrosine phosphorylation in a concentration-dependent
manner. AG490 inhibited CT-1–induced tyrosine
phosphorylation of STAT3 in a concentration-dependent
manner (Figure 4g) and inhibited CT-1–induced binding activity
of the STAT3 homodimer to the St-domain (Figure 4e).
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AT1 Receptor Antagonist Inhibits
CT-1–Induced Hypertrophy of Cardiac Myocytes
CT-1 (1 nmol/L) induced hypertrophy of cardiac
myocytes as indexed by [3H]-leucine
incorporation, protein content, and the protein-to-DNA ratio (Figure 5). The selective
AT1 receptor antagonist
losartan (1 µmol/L) significantly reduced
CT-1–stimulated increases in these indices of cardiac
hypertrophy (Figure 5). The Ang II type 2 receptor
antagonist PD123319 (10 µmol/L) had no effect on the
rate of accelerated protein synthesis (data not shown). These results
indicate that CT-1–stimulated hypertrophy of cardiac
myocytes is mediated, in part, by autocrine production of Ang
II and activation of the AT1 receptor.
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Discussion |
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The IL-6–related cytokine CT-1 is a potent inducer of cardiac myocyte hypertrophy and has been shown to activate the JAK/STAT pathway via the intermediate transmembrane signaling glycoprotein gp130.11 Continuous stimulation of gp130, with a transgenic approach in which IL-6 and soluble IL-6 receptors were overexpressed, resulted in cardiac hypertrophy.18 However, the downstream molecular mechanisms of CT-1– or gp130-induced cardiac myocyte hypertrophy remain to be elucidated. Our results describe a novel autocrine interaction between Ang II (G-protein–coupled receptor) and CT-1 (LIF receptor/gp 130) that affects cardiac myocyte growth. We found that CT-1 stimulated Ao gene expression by STAT3 activation and hypertrophy of neonatal rat ventricular myocytes, in part, by production of Ang II.
To the best of our knowledge, this is the first report of a
cytokine-inducing Ao gene upregulation through the JAK/STAT
pathway. Recently, Ang II was shown to stimulate Ao expression in
cardiac myocytes by activation of STAT3 and STAT6.9 STAT
proteins mediated this response through binding to the St-domain (bases
-160 to -175) in the promoter of the rat Ao gene. The St-domain
CTTCCTGGAAG9 shares similarity with the
consensus TTNCNNNAA sequence that binds STAT
proteins.5 In transient transfection experiments, we
observed that CT-1 transactivated the St-domain of the Ao gene
promoter. Even though STAT1, STAT3, and STAT5 were tyrosine
phosphorylated by CT-1 treatment of cardiac myocytes,
only STAT3 homodimer bound the St-domain of the Ao promoter, as
determined with an electrophoretic mobility shift assay. We found that
CT-1 induced activation of STAT3 and Ao promoter activity coupled
through JAK2. AG490 blocked CT-1 induced tyrosine
phosphorylation of STAT3, binding activity of STAT3
homodimer to the St-domain, and Ao promoter activity in cardiac
myocytes. CT-1 caused hypertrophic growth of neonatal rat cardiac
myocytes, as indexed by increases in protein synthesis, cellular
protein content, and the protein-to-DNA ratio. Hypertrophy
was markedly attenuated by 60% with losartan, an
AT1 receptor antagonist. This finding
indicates that CT-1–enhanced Ang II production induced cardiac
myocyte hypertrophy via an autocrine mechanism. Ang II is
known to induce cardiac myocyte hypertrophy via the
AT1 receptor.15 Autocrine mechanisms
have also been implicated in the hypertrophic actions of several
agonists on cardiac myocytes, including Ang II19 and
-adrenergic.20 Moreover, the hypertrophic response of
cardiac myocytes to uniaxial stretch, in vitro, is mediated by the
release of endothelin21 and/or Ang II.13 14
Similarly, in vivo pressure overload results in increased STAT
activity6 and Ao gene expression.22 Combined,
these data suggest a critical role for autocrine mechanisms, including
the JAK/STAT and cardiac RAS pathways, in the mediation of experimental
and pathological cardiac hypertrophy.
Although CT-1 increased Ao mRNA levels in cardiac myocytes, and AT1 receptor antagonist inhibited CT-1–induced cardiac myocyte hypertrophy, we were unable to detect an increase in Ang II levels (by ELISA, pmol/10 mL per 10x106 cells) in medium of cells treated with CT-1 for 24 hours (0.75±0.19 control versus 0.76±0.24 CT-1 treatment) or for 48 hours (1.60±0.73 control versus 1.65±0.77 CT-1 treatment). A similar observation was made for the mechanical stretch-induced hypertrophy of neonatal rat cardiac myocytes.14 In this model, it was shown that an AT1 receptor antagonist inhibited hypertrophy, although increased Ang II medium levels could not be detected by radioimmunoassay.14 Our inability (and others) to detect a change in Ang II levels in the medium is likely due to dilutional effects, because levels of Ang II at the plasma membrane should be substantially higher. The inhibitory effect of losartan on CT-1–induced hypertrophy strongly supports a mediating role for Ang II.
Evidence indicates that CT-1 has an important role in the process of ventricular remodelling. A significant elevation of plasma CT-1 was recently demonstrated in patients with heart failure.23 In addition, a heart-specific increase in CT-1 gene expression was found to precede the establishment of ventricular hypertrophy in genetically hypertensive rats.24 Interestingly, long-term treatment of these animals with the ACE inhibitor lisinopril prevented the development of left ventricular hypertrophy, without affecting ventricular CT-1 mRNA levels. This latter finding is consistent with our model that the hypertrophic actions of CT-1 are mediated in part through upregulation of cardiac Ao gene expression and Ang II production. Factors that upregulate cardiac CT-1 production have not been defined. Cardiac fibroblasts were recently shown to express 3.5 times more levels of CT-1 mRNA than cardiac myocytes.25 These investigators also found that CT-1 antibody significantly inhibited the increased gene expression and protein synthesis that is characteristic of hypertrophic growth of cardiac myocytes in coculture with cardiac fibroblasts. Release of CT-1 from cardiac fibroblasts may explain the recent observation16 that conditioned medium of cardiac fibroblasts elicits an increase in Ao mRNA levels of ventricular myocytes. Thus, CT-1 probably represents an important paracrine factor in the heart, affecting cardiac myocyte growth through production of cardiac Ang II.
In the present study, 
40% of the hypertrophic action of CT-1
could not be blocked by an AT1 receptor
antagonist. We would not have anticipated that all of the
hypertrophic actions of CT-1 would be mediated by autocrine
production of Ang II, because CT-1 and Ang II induce different
patterns of hypertrophic growth in cardiac myocytes.3 In
addition, gp130 was shown to couple to activation of
phosphatidylinositol 3-kinase, which has been linked to increased
protein synthesis in cardiac myocytes.26 It is also
important to note that autocrine production of Ang II is
unlikely to fully explain the consequences of STAT3 activation on
cardiac myocytes. Recent evidence indicates that gp130, and
specifically STAT3, are linked to a survival or antiapoptotic
pathway in cardiac myocytes that has been postulated to be important in
preventing the transition from compensatory hypertrophy to
heart failure.27 28 How the cardiac RAS interdigitates
with the gp130/STAT3 survival or antiapoptotic pathway awaits
to be defined.
In summary, we demonstrate that CT-1 induces cardiac myocyte hypertrophy, in part, by upregulation of Ao mRNA expression in cardiac myocytes, via STAT3 binding to the St-domain of the Ao gene promoter. CT-1–induced STAT3 tyrosine phosphorylation was mediated by JAK2. Moreover, an AT1 receptor antagonist attenuated CT-1–induced hypertrophy of neonatal rat cardiac myocytes, suggesting that upregulation of Ao and Ang II production contribute to CT-1–induced cardiac myocyte hypertrophy. These findings emphasize the importance of an interaction between G-protein–coupled and cytokine receptors in the mediation of cardiac myocyte growth.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (HL-44883, HL-58439, and HL-60529 to K.M.B.). Dr Baker is an Established Investigator of the American Heart Association. The expert technical assistance of Anna M. Kempinski (Pennsylvania State University College of Medicine) was greatly appreciated.
Received February 25, 2000; first decision March 13, 2000; accepted April 5, 2000.
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 R. J. Gusterson, E. Jazrawi, I. M. Adcock, and D. S. Latchman The Transcriptional Co-activators CREB-binding Protein (CBP) and p300 Play a Critical Role in Cardiac Hypertrophy That Is Dependent on Their Histone Acetyltransferase Activity J. Biol. Chem., February 21, 2003; 278(9): 6838 - 6847. [Abstract] [Full Text] [PDF]
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J. Fukuzawa, J. Nishihira, N. Hasebe, T. Haneda, J. Osaki, T. Saito, T. Nomura, T. Fujino, N. Wakamiya, and K. Kikuchi Contribution of Macrophage Migration Inhibitory Factor to Extracellular Signal-regulated Kinase Activation by Oxidative Stress in Cardiomyocytes J. Biol. Chem., July 5, 2002; 277(28): 24889 - 24895. [Abstract] [Full Text] [PDF]
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 T. Tsuruda, M. Jougasaki, G. Boerrigter, B. K. Huntley, H. H. Chen, A. B. D'Assoro, S. C. Lee, A. M. Larsen, A. Cataliotti, and J. C. Burnett Jr Cardiotrophin-1 Stimulation of Cardiac Fibroblast Growth: Roles for Glycoprotein 130/Leukemia Inhibitory Factor Receptor and the Endothelin Type A Receptor Circ. Res., February 8, 2002; 90(2): 128 - 134. [Abstract] [Full Text] [PDF]
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 E. Mascareno, M. El-Shafei, N. Maulik, M. Sato, Y. Guo, D. K. Das, and M.A.Q. Siddiqui JAK/STAT Signaling Is Associated With Cardiac Dysfunction During Ischemia and Reperfusion Circulation, July 17, 2001; 104(3): 325 - 329. [Abstract] [Full Text] [PDF]
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G. B. Ehret, P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz, and P. Bucher DNA Binding Specificity of Different STAT Proteins. COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES J. Biol. Chem., February 23, 2001; 276(9): 6675 - 6688. [Abstract] [Full Text] [PDF]
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R. Gusterson, B. Brar, D. Faulkes, A. Giordano, J. Chrivia, and D. Latchman The Transcriptional Co-activators CBP and p300 Are Activated via Phenylephrine through the p42/p44 MAPK Cascade J. Biol. Chem., January 18, 2002; 277(4): 2517 - 2524. [Abstract] [Full Text] [PDF]
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 Y. Takimoto, T. Aoyama, Y. Iwanaga, T. Izumi, Y. Kihara, D. Pennica, and S. Sasayama Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H896 - H901. [Abstract] [Full Text] [PDF]
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T. Tsuruda, M. Jougasaki, G. Boerrigter, B. K. Huntley, H. H. Chen, A. B. D'Assoro, S. C. Lee, A. M. Larsen, A. Cataliotti, and J. C. Burnett Jr Cardiotrophin-1 Stimulation of Cardiac Fibroblast Growth: Roles for Glycoprotein 130/Leukemia Inhibitory Factor Receptor and the Endothelin Type A Receptor Circ. Res., February 8, 2002; 90(2): 128 - 134. [Abstract] [Full Text] [PDF]
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