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1 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan 606-8507; 2 Hypertension Research Laboratory, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka, Japan 565-8565; and 3 Department of Anesthesiology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan 606-8507
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Cardiotrophin-1
(CT-1), a member of the interleukin-6 superfamily of cytokines,
possesses hypertrophic actions and atrial natriuretic peptide
(ANP)-producing activity in vitro. The goal of our study is to
elucidate whether CT-1 affects the cardiovascular system in vivo.
Intravenous injection of CT-1 (4-100 µg/kg) in conscious rats
evoked significant declines in blood pressure and reflex increases in
heart rate (HR) in a dose-dependent manner. CT-1 induced no significant
change in cardiac output (from 260.7 ± 11.0 to 264.7 ± 26.6 ml · min
1 · kg1,
P = not significant), which was compatible with the results from isolated perfused rat hearts; HR, change in pressure over time, left ventricular developed pressure, and perfusion pressure were
unaffected. Northern blot and RT-PCR analyses revealed that CT-1
increased expression of inducible nitric oxide synthase (iNOS) in lung
and aorta but not in heart or liver. Pretreatment with aminoguanidine,
a specific iNOS inhibitor, inhibited both iNOS mRNA production and the
depressor effect of CT-1. Interestingly, CT-1 increased ventricular
expression of ANP and brain natriuretic peptide (BNP). The data
demonstrate that CT-1 elicits its hypotensive effect via a nitric
oxide-dependent mechanism and that CT-1 induces ANP and BNP mRNA
expression in vivo.
blood pressure; nitric oxide synthase; natriuretic peptide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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GROWING EVIDENCE INDICATES that humoral
factors such as angiotensin II (ANG II) (35), endothelin-1 (17, 27),
and 
-adrenergic receptor agonists (32) play obligatory roles in the
pathogenesis and progression of ventricular remodeling and subsequent
heart failure. These agents are all G protein-coupled receptor agonists that exert their cardiovascular actions, which include
vasoconstriction, positive inotropy, and myocyte hypertrophy, by
activating a mitogen-activated protein (MAP) kinase family pathway
(26).
It has recently become apparent that another class of humoral factors,
the cytokines, are also overexpressed during such human cardiac-related
illnesses as congestive heart failure, ischemic heart disease, dilated
cardiomyopathy, and septic cardiomyopathy (2, 16, 37). One
well-characterized cytokine that functions significantly in the
pathology of cardiac disease is tumor necrosis factor- (TNF-),
which is in part synthesized in the heart itself. Bolus injection of
TNF- induces nitric oxide synthase (NOS) activation by nuclear
factor-
B (NF-B) (13, 15, 38) and nitric oxide (NO)-dependent
decreases in arterial blood pressure and contractility.
Interleukin-6 (IL-6) is another multifunctional cytokine that mediates immune and inflammatory responses; plasma levels of IL-6 are reported to be elevated in cases of acute myocardial infarction, cardiac hypertrophy, and congestive heart failure (36, 40). IL-6 binding to its receptor and subsequent formation of the gp130 receptor complex activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in target cells. Although gp130 is abundant in the heart, little or no IL-6 or its receptor are expressed there. Accordingly, direct effects of IL-6 on the heart are not considered to be important. In fact, it was reported previously that injection of IL-6 in the dog did not alter the hemodynamic parameters (25). Nonetheless, several lines of evidence indicate the importance of the gp130 signaling pathway in cardiac development and cardiac myocyte hypertrophy. For example, transgenic mice overexpressing IL-6 and soluble IL-6 receptors showed myocardial hypertrophy. Disruption of the gene for gp130 was lethal in mice, and these mice demonstrated hypoplastic ventricular myocardium (5, 42).
Cardiotrophin-1 (CT-1) is a member of the IL-6 superfamily and was isolated from mouse embryoid body based on its ability to induce cardiac myocyte hypertrophy in vitro (22, 24). Substantial levels of CT-1 have been detected in the heart as well as in the kidney, lung, and aorta, and in skeletal muscle (7). In the heart, CT-1 mRNA is expressed both in myocytes and in surrounding nonmyocytes (12); it binds to the gp130/leukemia inhibitory factor (LIF) receptor complex in cardiac myocytes and activates the JAK-STAT and MAP kinase pathways (41). We previously showed that the expression of CT-1 mRNA is upregulated in the hypertrophied ventricles of genetically hypertensive rats (7). Moreover, using a specific anti-CT-1 antibody, we observed that CT-1 is released primarily from nonmyocytes and induces enlargement of myocyte size and atrial and brain natriuretic peptide (ANP and BNP, respectively) production in vitro (11, 30). The aim of the present study is to clarify whether CT-1 affects hemodynamics and endocrine function of the heart in vivo.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Male Wistar rats (250-270 g, Shimizu Experiment, Tokyo) were housed in a light- and temperature-controlled room; they received rat chow and water ad libitum.
Reagents. Recombinant rat CT-1 was prepared using the glutathione S-transferase (GST) fusion system described in an earlier work (7). Briefly, the open reading frame of rat CT-1, which we previously cloned, was inserted into the EcoR I site of the pGEM-4T3 expression vector (Amersham Pharmacia Biotech, Uppsala, Sweden). The GST fusion protein was expressed in bacteria, purified using a glutathione affinity column according to the manufacturer's instruction (Amersham), and cleaved by thrombin. The purity of the CT-1 was verified by SDS-PAGE and quantified by colorimetric assay (Bio-Rad Laboratories, Hercules, CA).
The specific NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG), and rat recombinant LIF were purchased from Sigma Chemical (St. Louis, MO).Measurement of systemic arterial pressure. Systemic arterial blood pressure (BP) was measured in anesthetized and conscious animals as described in a previous work (21). Initially, rats were anesthetized by intraperitoneal injection of 50 mg/kg pentobarbital sodium (Abbott). A polyethylene-50 catheter (PE-50) filled with heparin and saline (200 IU/ml) was then implanted in the right internal carotid artery, and a second PE-50 catheter was implanted in the right external jugular vein. These catheters were passed subcutaneously to the back of the neck, where they were exteriorized and plugged with stainless steel pins. The incisions were then closed with sutures, and the animals were allowed to regain consciousness. Arterial BP was then measured using a pressure transducer (Fukuda Denshi, Tokyo) connected to the arterial cannula.
Administration of CT-1. CT-1 at concentrations of 4, 20, and 100 µg/kg body wt in 100 µl of phosphate-buffered saline (PBS) was injected via the intravenous catheter, and BP was monitored for 60 min. Control rats received an equal volume of PBS alone.
Measurement of cardiac output. Cardiac output was measured using the thermodilution method under pentobarbital sodium anesthesia. A thermomicroprobe connected to a computerized cardiac output monitor (Cardiotherm-500, Columbus Instruments) was advanced into the ascending aorta via the right carotid artery. To measure cardiac output, 0.1 ml of 0.9% saline at room temperature was injected as a bolus via the intravenous catheter (18). Measurements were made in triplicate shortly before and 15 min after CT-1 administration.
Isolated heart procedure.
Rats were intraperitoneally injected with heparin (500 IU/kg) to block
coagulation and then killed. The hearts were quickly removed and
immersed in ice-cold perfusion fluid (modified Krebs-Henseleit solution). The aorta was canulated superior to the aortic valve, and
the isolated hearts were perfused at a constant rate of 6 ml/min at
37°C using the Langendorff technique without electrical pacing
(31). Electrocardiograms and coronary perfusion pressures were
monitored throughout the experiments using a San-Ei Biophysiograph 180 system (NEC San-Ei, Tokyo, Japan). Hearts were perfused for 60 min to
allow stabilization; if arrhythmia was observed during the
stabilization period, the heart was discarded. There was then a 30-min
control period, after which hearts were perfused for 30 min with
perfusion media alone (n = 10) or containing
109 (n = 9) or
108 (n = 5) mol/l of CT-1.
Isometric tension in aortic rings. Descending thoracic aorta was excised from rats euthanized by ether inhalation. The aorta was cleaned of adherent connective tissue and cut into transverse rings 4 mm in length. The rings were suspended between parallel hooks in a 10-ml tissue bath filled with Krebs-Henseleit solution at 37°C. A resting tension of 1.0 g was applied. Changes in isometric tension elicited by bath application of various drugs were recorded.
Intracerebroventricular injection of CT-1. Rats were anesthetized by intraperitoneal injection of pentobarbital sodium. A stainless-steel intracerebroventricular cannula was placed 6.5 mm anterior to the lambdoid suture and 1.4 mm lateral to the midline at a depth of 4.5 mm, as described in a previous work (28). Using a microsyringe injector, we injected 5 µg of CT-1 in 10 µl of PBS.
RNA extraction.
At selected times (shortly before injection and 15 min, 60 min, 2 h, 4 h, and 24 h after injection of CT-1), the lung, heart (left ventricle),
liver, and aorta were removed from the rats and frozen at
80°C. Tissues were later homogenized in Trizol reagent
(GIBCO BRL, Life Technologies, Grand Island, NY), and total RNA was
isolated according to the manufacturer's instructions.
Northern blot analysis. Northern blot analysis was performed as described in a previous work (19). Briefly, 20 µg of total RNA from each sample was separated on a 1.4% denaturing agarose gel and transferred onto nylon filters. The filters were incubated for 4 h at 42°C in prehybridization buffer consisting of 50% formamide, 5× Denhardt solution, 5× sodium-saline phosphate EDTA buffer, and 0.1% sodium dodecyl sulfate. The RNA on the filters was then hybridized for 24 h at 42°C to 32P-labeled probes at concentrations of 0.5 to 1 × 106 cpm/ml.
RT-PCR analysis. First-strand cDNA synthesis was performed with 5 µg of total RNA isolated from the aorta using Superscript II (GIBCO BRL) according to the manufacturer's instructions. The resulting cDNA was amplified by RT-PCR using the following iNOS primers: sense, 5'-CCCTT CCGAA GTTTC TGGCA GCAGC-3', and antisense, 5'-GGCTG TCAGA GCCTC GTGGC TTTGG-3'. The protocol consisted of 35 cycles of incubation at 94°C for 45 s, 65°C for 45 s, and 72°C for 2 min followed by extension for 7 min at 72°C. The amplified iNOS product (693 bp) was analyzed by 2% agarose gel electrophoresis and visualized by ethidium bromide staining under ultraviolet light.
Statistical analysis. All values are presented as means ± SE. Comparisons between two groups were completed with use of unpaired Student's t-tests. ANOVA with subsequent Fisher exact test was used to determine significant differences among three or four groups. A value of P < 0.05 was considered 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 intravenous infusion of CT-1 on hemodynamics in vivo in
conscious rats.
Intravenous injection of recombinant CT-1 (4 to 100 µg/kg) evoked
dramatic decreases in mean BP in conscious rats (Fig.
1A). At each dose BP began to
decline within 1 to 1.5 min after injection, and the response was
maximal within 10 min. BP subsequently returned almost to baseline
levels over the course of 60 min. Heart rate (HR) showed reactive
tachycardia in response to the decrease in BP (Fig. 1B).
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1 · kg1,
and it did not change after injection of 20 µg/kg CT-1 (264.7 ± 26.6 ml · min1 · kg1;
n = 3). As a control, we also measured BP and HR in rats with CT-1 injection. Mean BP significantly declined from 108.7 ± 0.67 to
71.7 ± 1.67 mmHg, although HR did not change (393.3 ± 45.5 vs.
397.7 ± 50.6 beats/min). Consequently, the calculated systemic vascular resistance (SVR) also decreased significantly (1.34 ± 0.06 vs. 0.88 ± 0.08 mmHg · min · ml1).
The magnitudes of the declines in BP were greater in anesthetized rats
than in conscious rats (compare Figs. 1A and 3A), most
likely due to the attenuation of the baroreceptor-reflex tachycardia present in conscious animals, which was absent in pentobarbital sodium-anesthetized animals.
To further investigate the mechanism of CT-1-induced systemic
hypotension, 10 mg/kg of L-NAME, a well-characterized NOS
inhibitor, was intravenously injected 15 min before CT-1
administration. Pretreatment with L-NAME completely
inhibited the depressor response to 20 µg/kg CT-1 (Fig.
3B, Table
1). Because L-NAME elevated BP
by as much as 20%, in the present experiments the rats were instead
pretreated with 4 mg/kg of ANG II, which elevated BP to the same
degree. In the presence of ANG II, CT-1 decreased BP to the same degree
as observed without pretreatment (data not shown).
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Isolated rat heart.
To clarify the direct effects of CT-1, isolated rat hearts were
perfused with and without 109 and
108 mol/l CT-1 for 30 min using the
Langendorff technique. CT-1 had no effect on HR, maximum change in
pressure over time (dP/dt), left ventricular developed pressure
(LVDP), or perfusion pressure (Fig. 4). In
contrast, 106 mol/l propranorol
hydrochloride, a 
-blocking agent, decreased HR, LVDP, and maximum
dP/dt significantly (Fig. 4), indicating the validity of our
Langendorff apparatus. Thus CT-1 had no direct chronotropic or
inotropic effect on the heart.
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Intracerebroventricular injection of CT-1. To rule out a central nervous system-mediated hypotensive effect, 20 µg/kg CT-1 was injected into the cerebral ventricles. There was no change in mean BP during the 30-min period following intracerebroventricular injection of CT-1 (data not shown). Via the same catheter, 10 µg/kg of pentobarbital sodium was administered 30 min after the CT-1 injection. BP decreased rapidly and transiently, suggesting that the intracerebroventricular catheter was correctly located, although 10 µg/kg of pentobarbital sodium never affected BP when it was administered peripherally.
Isometric tension in aortic rings.
The capacity of L-NAME to completely block the hypotensive
effect of CT-1 strongly suggested that NO was involved in the response. To assess the role of endothelial NOS (eNOS), we tested the effects of
CT-1 in aortic ring preparations with and without intact endothelium. Under 1 g of resting tension, the aortic rings with intact endothelium were precontracted with 108 and
107 mol/l norepinephrine (NE) by 0.61 ± 0.07 and 0.95 ± 0.10 g (P < 0.05), respectively. The
rings were then promptly relaxed by the administration of
108 mol/l ACh by 47.2 ± 7.5% of the precontracted level by 107
mol/l NE, indicating that endothelial function was retained normally in
the ring preparation. Administration of
108 and
107 mol/l CT-1, by contrast, did not
relax the precontracted rings significantly (3.5 ± 4.8% and 2.6 ± 1.9%, respectively), nor did it relax endothelium-denuded ring
preparations (data not shown). This may mean that eNOS is unaffected by
CT-1 and/or that CT-1 reduces SVR by acting specifically on resistance
vessels and has no effect on large elastic arteries.
Analysis of iNOS mRNA expression.
Because eNOS was apparently not involved in the response to CT-1,
alternative NOS activation was presumed. To test this hypothesis, expression of iNOS mRNA in CT-1-treated rats was analyzed by Northern blot in tissue samples from the lung, liver, heart, and spleen, and by
RT-PCR in the aorta. Expression of iNOS mRNA was significantly increased in the lung (Fig. 5A) and
aorta (Fig. 5B) 60 min after CT-1 administration, compared with
that of rats injected with the same volume of PBS (Fig. 5B); no
detectable increase in expression was present after 15 min.
Interestingly, CT-1 had no effect on expression of iNOS mRNA in the
heart (Fig. 5A).
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Expression of mRNA for ANPs and BNPs.
Our data show that the pharmacological dose of CT-1 has no effect on
hemodynamic parameters in the heart. However, because CT-1 stimulates
ANP and BNP synthesis and secretion in cultured ventricular myocytes
(6), we investigated whether or not CT-1 affected ventricular
expression of ANP and BNP mRNA in vivo. Figure 7 shows that expression of BNP mRNA was
significantly augmented 1 h after injection of CT-1, reached a maximum
2 h after injection, and returned to the baseline levels within 24 h.
Interestingly, ANP mRNA was not changed significantly until 24 h after
the injection, and thereafter it was increased.
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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 demonstrates that intravenous administration of CT-1 causes dose-dependent systemic hypotension in both conscious and anesthetized rats via a NO-dependent mechanism. Cardiac output was unaffected by CT-1; moreover, results from experiments carried out in isolated hearts showed that there was no direct suppressive effect of CT-1 on cardiac function. Rather, the hypotensive effect resulted from a significant decline in SVR caused by NO-evoked vasodilation. We also showed for the first time that LIF elicits a hypotensive response that is virtually identical to that of CT-1. Because CT-1 and LIF share the LIF/gp130-receptor heterodimer complex, and both activate the JAK-STAT pathway, it is likely that the hypotension is a common effect of agonists sharing the LIF/gp130-receptor heterodimer complex signaling pathway.
The present study indicates that CT-1 did not directly affect cardiac
function itself in vivo and in vitro. In isolated perfused hearts, CT-1
had no inotropic or chronotropic effects. In conscious rats, HR
increased after CT-1 injection, almost certainly due to baroreceptor
reflex to the decrease in BP. Cardiac output was not changed in vivo.
These findings are consistent with the recent data from Jim et al. (9)
in which it is mentioned that CT-1 does not induce a change in either
calculated stroke volume or ventricular contractility. The doses we
used in the isolated perfused hearts are considered valid, because CT-1
induces myocyte hypertrophy and ANP and BNP production in cultured
media in a dose-dependent manner at a range from
1011 to
108 mol/l. Moreover,
109 mol/l of CT-1 induces
phosphorylation of signal transducers and activators of transcription-3
(STAT-3) in myocytes (11). The doses we used for in vivo studies are
also considered valid, because plasma CT-1 concentrations are probably
~108 mol/l just after injection of 20 µg/kg of CT-1 intravenously, when the plasma volume is taken into account.
It was also possible that the intravenously administered peptide directly acted on the central nervous system; this is the case for leptin (1, 4), a newly discovered satiety factor whose receptor is also a member of the gp130 family (20). However, no significant changes in systemic hemodynamics were observed when CT-1 was intracerebroventricularly injected, indicating that the site of action of intravenously administered CT-1 is the cardiovascular system in the periphery.
Our finding that CT-1-induced hypotension was completely blocked by
L-NAME is indicative of the role played by NOS. As is well
known, three different types of NOS are recognized: eNOS, iNOS, and
neuronal NOS. Many growth factors and cytokines cause hypotension by
activating eNOS or iNOS. Platelet-derived growth factor BB causes an
endothelium-dependent, NO-mediated relaxation of rat aorta (3), and
insulin-like growth factor 1 induces NO production in endothelial cells
by activating eNOS (39). In this context, first we assessed the
endothelium dependence of CT-1-induced hypotension in aortic ring
preparations and found none. Furthermore, we detected no nitrite
production in cultures of bovine aortic endothelial cells after CT-1
stimulation by the Greise method (data not shown). Thus it appears
unlikely that eNOS-mediated vasorelaxation was involved in the response
to CT-1. To clarify the next possibility, we assessed iNOS expression
because it is well established that inflammatory cytokines such as
interleukin-1 (22) and TNF- (15) cause vasorelaxation by inducing
iNOS. Indeed, we observed augmented expression of iNOS mRNA in the
aorta and lung 60 min after CT-1 administration, suggesting the
possible participation of iNOS in the hypotensive effect of CT-1.
Furthermore, our data using the iNOS-specific inhibitor AG strengthened
this conclusion. However, there was a discrepancy in the time courses between CT-1-induced hypotension and expression of iNOS mRNA: systemic
hypotension developed within several minutes, whereas increases in iNOS
were not detectable for 60 min after the CT-1 injection. Considering
that even in the case of lipopolysaccharide (LPS)-induced hypotension
(which is recognized to be mediated by iNOS induction), the mRNA level
of iNOS upregulation was just detectable more than 1 h after LPS
injection (14), and this discrepancy could be accounted
for. Furthermore although TNF- increases iNOS mRNA
expression in many organs, including the heart, and thereby induces
ventricular dysfunction (10, 29), iNOS mRNA was selectively upregulated
by CT-1 in the aorta and lung but not in the heart or liver. The
absence of an effect on perfusion pressure, LVDP, and maximum
dP/dt by CT-1 on the isolated heart is consistent with the
finding that the expression of iNOS mRNA was not upregulated in the
heart. Consequently, although it is evident that CT-1-induced
hypotension is NO mediated, further studies will be necessary to
clarify the precise site of action and mechanism for CT-1-induced vasorelaxation.
Of particular interest to us was the finding that CT-1 affects endocrine function, or ANP and BNP production, although it does not affect the cardiac pumping function, as mentioned above. As previously reported, CT-1 stimulates ANP and BNP secretion and increases cell size in cultured ventricular myocytes (6, 11, 24). Until now, most humoral stimulators for ANP and BNP secretion, such as G protein-coupled receptor agonists, increased loading conditions in vivo when they were intravenously injected (8). In this point, CT-1 seems to be another class of stimulator for ANP and BNP and probably has different roles than G protein-coupled receptor agonists in the cardiovascular system. It is not clear what the precise mechanism is for the upregulation of ANP and BNP production by CT-1 in vivo, nor whether it includes the direct or indirect action of CT-1. However, considering that CT-1 stimulates ANP and BNP secretion in vitro and that CT-1 does not affect cardiac pumping function for at least 1 h after injection in vivo, it may be possible that CT-1 stimulates ANP and BNP production in vivo independent of hemodynamic changes. The significance of increased expression of ANP and BNP genes by CT-1 is not clear at present. Although ANP and BNP have hypotensive properties in vivo, it is unlikely that ANP and BNP play an obligatory role in the decrease in blood pressure by CT-1 infusion, because the hypotensive effect of ANP and BNP is not blocked by L-NAME.
Recently Talwar et al. (34) demonstrated that plasma CT-1 concentration is upregulated in patients with heart failure. Considering this finding and our present data, CT-1 may play a part in reducing afterload in certain pathological conditions. To understand the precise role of endogenous CT-1 or the long-term effects of CT-1, the development of mice lacking or overexpressing the CT-1 gene is needed in the near future.
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ACKNOWLEDGEMENTS |
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We thank Dr. Narumiya and Dr. Ushikubi for support in the experiment using isolated aortic rings, and we thank Dr. Katsuura for technical support and advice in the experiment of the central effect of CT-1 on blood pressure. We also thank T. Okumura and M. Yamashita for excellent secretarial work.
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FOOTNOTES |
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This work was supported in part by research grants from the Japanese Ministry of Education, Science and Culture, the Japanese Ministry of Health and Welfare, Research for the Future program of the Japan Society for the Promotion of Science (JSPS-RFTF96I00204 and 98L00801), grants from the Japanese Cardiovascular Research Foundation, and the Smoking Research Foundation.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: Y. Saito, Dept. of Medicine and Clinical Science, Kyoto Univ. Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan 606-8507 (E-mail: yssaito{at}kuhp.kyoto-u.ac.jp).
Received 8 March 1999; accepted in final form 15 December 1999.
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RESULTS
DISCUSSION
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, n = 5), 4 µg/kg
CT-1 (
, n = 5), 20 µg/kg CT-1 (
, n = 5), and
100 µg/kg CT-1 (
, n = 4); *P < 0.01 vs. baseline
BP, 
P < 0.01 vs. control reagent.
),
10
