Ann Thorac Surg 2003;76:237-243
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Cardiotrophin-1 is a prophylactic against the development of chronic hypoxic pulmonary hypertension in rats
Norikazu Nomura, MDa,
Miki Asano, MDa,
Takayuki Saito, MDa,
Shigeru Sasaki, MDa,
Hikaru Suzuki, PhDb,
Tadao Manabe, MDc,
Akira Mishima, MDa*
a Department of Cardiovascular Surgery, Nagoya, Japan
b Department of Regulatory Cell Physiology, Nagoya, Japan
c Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Accepted for publication February 12, 2003.
* Address reprint requests to Dr Mishima, Department of Cardiovascular Surgery, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
e-mail: mishima{at}med.nagoya-cu.ac.jp
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Abstract
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BACKGROUND: Cardiotrophin-1 (CT-1) reduces arterial blood pressure by activating nitric oxide synthesis. This study attempted to elucidate the effect of CT-1 on pulmonary arteries of pulmonary hypertensive rats.
METHODS: Pulmonary hypertension was induced in rats in a hypoxic chamber containing 10% to 11% oxygen. Rats kept in the hypoxic environment received either recombinant mouse CT-1 at a concentration of 50 µg/kg (CT-1+hypoxia group, n = 21) or phosphate-buffered saline (hypoxia group, n = 30) once per day. Control rats housed in room air also received either the equivalent concentration of CT-1 (CT-1+normoxia group, n = 18) or phosphate-buffered saline (normoxia group, n = 39). Pulmonary arterial pressure, pulmonary vasorelaxation, and ventricular hypertrophy were measured.
RESULTS: The mean pulmonary arterial pressures were as follows (from lowest to highest; p values are relative to the hypoxia group): normoxia group (20.3 ± 4.0 mm Hg, p < 0.0001), CT-1+normoxia group (21.1 ± 2.4 mm Hg, p < 0.0001), CT-1+hypoxia group (27.9 ± 4.1 mm Hg, p = 0.0019), and hypoxia group (33.9 ± 6.6 mm Hg). The endothelium-dependent vasorelaxation value was largest in the normoxia group (59.5% ± 17.4%, p < 0.0001), with it decreasing in the other groups in the following order (p values are relative to the hypoxia group): CT-1+normoxia group (52.8% ± 15.5%, p = 0.0005), CT-1+hypoxia group (42.3% ± 14.8%, p = 0.0061), and hypoxia group (17.4% ± 4.8%). Right ventricular hypertrophy was significant only in the hypoxia group.
CONCLUSIONS: Our results demonstrate that treatment with CT-1 in a chronic hypoxic pulmonary hypertension model protects the endothelial function of the pulmonary artery; decreases pulmonary arterial pressure; and attenuates right ventricular hypertrophy.
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Introduction
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Pulmonary hypertension is a poor prognostic factor in patients with congenital heart disease, and hence its management is important. The inhalation of nitric oxide (NO) gas is used in such patients; however, long-term inhalation of NO gas has some limitations due to the production of nitrogen dioxide and the possible outbreak of methemoglobinemia. Therefore, alternative generators of NO with high selectivity to pulmonary arterial pressure or pulmonary vascular resistance need to be developed.
Recent studies have demonstrated that some cytokines, such as cardiotrophin-1 (CT-1) [1], and interleukin-2 [2], activate NO synthesis and hence induce NO-dependent decreases in arterial blood pressure. Furthermore, CT-1 therapy is effective against the accumulation of neutrophils and pulmonary vasoconstriction in endotoxin-induced acute lung injury [3]. However, little information is available about whether CT-1 acts on the endothelium of the pulmonary artery, and whether it is effective for pulmonary hypertension.
Cardiotrophin-1 has been identified as a member of the interleukin-6 superfamily of cytokines, which includes interleukin-6, interleukin-11, leukemia inhibitory factor, oncostain M, and ciliary neurotrophic factor [4]. The CT-1 receptor is a dimer comprising a leukemia inhibitory factor receptor and a glycoprotein 130 [5]. The CT-1 activates a number of signaling pathways in cardiac myocytes through the receptor, including the Janus kinase/signal transducers and activators of transcription-3 pathway and the mitogen-activated protein kinases pathway [5, 6]; CT-1 protects the function of cardiac myocytes and maintains systemic circulation by autocrine effects [7, 8].
We have a great interest in CT-1 as a possible effective therapy for pulmonary hypertension in patients with congenital heart disease. Here we studied whether CT-1 enhances the function of the endothelium in the pulmonary artery to decrease pulmonary arterial pressure in chronic hypoxic and hypertensive immature rats.
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Material and methods
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Pretreatment of animals
The study used 4-week-old male Wistar rats (SLC, Hamamatsu, Japan) weighing 112.2 ± 7.8 g (range 98.3 to 130.1 g). We defined 4-week-old rats as immature for the following reasons: (1) the vascular tone of such rats, which are developmentally similar to 1- to 2-year-old infants, is more sensitive than that in older rats [9]; (2) the fertility of 4-week-old rats is not mature; and (3) previous studies have also considered 4-week-old rats as immature [9, 10]. Rats were assigned to one of four groups. Rats in two of the groups were kept in a hypoxic chamber containing 10% to 11% oxygen for 9 days and received, by intraperitoneal injection once per day, either recombinant mouse CT-1 at a concentration of 50 µg/kg in 200 µL of phosphate-buffered saline (CT-1+hypoxia group, n = 21), or an equal volume of phosphate-buffered saline (hypoxia group, n = 30). The age-matched rats in the other two groups were housed in room air for the same period and received either recombinant mouse CT-1 at the equivalent concentration as the CT-1+hypoxia group (CT-1+normoxia group, n = 18) or 200 µL of phosphate-buffered saline (normoxia group, n = 39) in the same manner. Administration of the drug began on the first day of exposure to hypoxic conditions or ambient air, and continued until the ninth day of the exposure. The mixture of nitrogen and air was continuously flushed in the hypoxic chamber at the rate of 2.0 L/min, with the amount of nitrogen in the air adjusted to keep the oxygen component of the gas in the chamber within the range 10% to 11% (Oxygen-level control chamber; 1550, Waken Electronics, Kyoto, Japan) [11]. Soda lime was included in the chamber to prevent the accumulation of carbon dioxide. These rats were removed from the chamber for 15 minutes each day for their injections, replenishment of food and water supplies, and cleaning of the chamber. Food and water were provided ad libitum during the experiment. We divided each group into two subgroups to study pulmonary hemodynamics and vasorelaxation, respectively. This study was approved by the Institutional Animal Care and Use Committee of Nagoya City University and conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.
Measurement of pulmonary arterial pressure
Rats were anesthetized with pentobarbital sodium (33 mg/kg) by intraperitoneal injection and artificially ventilated by tracheal cannulation. A heparin-filled 23-gauge polyurethane catheter was inserted into the right internal carotic artery for monitoring systemic arterial pressure. The thorax was opened by median sternotmy. A hypodermic 27-gauge needle was inserted into the outlet tract of the right ventricle and advanced into the main pulmonary artery [12]. Systemic arterial pressure and pulmonary arterial pressure were measured with a pressure transducer (TC2309S; Edwards Lifesciences, Irvine, CA), an amplifier system (AU-5003; Fukuda Denshi, Tokyo, Japan), and a visualization system (DS-1060; Fukuda Denshi). Mean pulmonary arterial pressure, mean systemic arterial pressure, and heart rate were measured, and the ratio of the systolic pressures of the pulmonary and systemic arteries (Pp/Ps) was calculated.
Preparation of isolated pulmonary arterial ring
The lung and heart were removed en bloc and soaked in Krebs solution at room temperature after similar anesthesia. The composition of the solution was as follows (in mM): NaCl, 122.0; KCl, 4.7; CaCl2, 2.6; MgCl2, 1.2; NaHCO3, 15.5; KH2PO4, 1.2; and D-glucose, 11.5. An intralobar left pulmonary artery was gently dissected out from the tissue surrounding the vessel. A length of isolated pulmonary arterial ring segment (1.5 to 2.0 mm) was harvested. The ring segment was mounted between two stainless-steel wires in organ baths containing Krebs solution at 37°C, and bubbled with a mixture of 95% oxygen and 5% carbon dioxide. One of the wires was anchored and the other was connected to a force-displacement transducer (TB-612T; Nihon Kohden, Tokyo, Japan) to measure the changes in isometric force [13]. The mechanical responses were recorded on a pen recorder (VP-6524A; National, Osaka, Japan).
Examination of pulmonary vasorelaxation
A ring preparation was equilibrated for 1 hour at resting tension. Cumulative concentration-response curves were obtained over the concentration range of 10-9 M to 10-5 M for acetylcholine (ACh) or sodium nitroprusside (SNP). A ring preparation was contracted with noradrenaline at a concentration of 10-6 M, exposed to the lowest dose of each drug, and then the degree of relaxation was measured. The results are evaluated as percentage relaxation of the noradrenaline-induced precontraction. After reaching a stable resting tension by washing with Krebs solution, the sample was precontracted with noradrenaline at the same concentration again before the addition of the next higher concentration of ACh or SNP.
Measurement of body weight and ventricular hypertrophy
Rats were weighed three times during the experiment: at the start, on the sixth day, and before measurement of hemodynamic values on the tenth day.
The heart removed for the previous examinations was weighed. Then the free wall of the right ventricle (RV) was dissected from the left ventricle plus intraventricular septum (LV+S), and the two parts were weighed separately (RV and LV+S, respectively). The following ratios were calculated: right ventricle weight to left ventricle plus intraventricular septum weight [RV/(LV+S)], and right ventricle weight to body weight (RV/BW).
Reagents
The following drugs were purchased: recombinant mouse CT-1 (Genzyme; Techne, Minneapolis, MN); and ACh, SNP, and noradrenaline hydrochloride (Sigma, St. Louis, MO). Note that the amino-acid sequences of mouse CT-1 are 94% homologous with those of rat CT-1 [14]. Recombinant mouse CT-1 was diluted with sterile phosphate-buffered saline. The concentrations of the drugs are expressed as final molar concentrations in the organ bath.
Statistical analysis
Data are presented as means ± standard deviations. Differences among the groups in concentration–response (relaxation) curves and changes in BW were determined by analysis of variance (ANOVA) with repeated measures followed by the posthoc Bonferroni–Dunn test. Hemodynamics data and weight-parameter ratios were analyzed by one-way ANOVA followed by the posthoc Bonferroni–Dunn test. The p values less than 0.05 were taken to indicate significant differences.
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Results
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Hemodynamic studies
Treatment with CT-1 under the hypoxic conditions significantly reduced the mean pulmonary arterial pressure and Pp/Ps value (Fig 1).
Rats in the hypoxia group exhibited significant pulmonary hypertension. The mean pulmonary arterial pressure in the hypoxia group (33.9 ± 6.6 mm Hg) was significantly higher than in the other three groups: normoxia group (20.3 ± 4.0 mm Hg, p < 0.0001), CT-1+normoxia group (21.1 ± 2.4 mm Hg, p < 0.0001), and CT-1+hypoxia group (27.9 ± 4.1 mm Hg, p = 0.0019). In addition, Pp/Ps in the hypoxia group (0.40 ± 0.09) was significantly higher than in the other three groups: CT-1+normoxia group (0.23 ± 0.03, p < 0.0001), normoxia group (0.26 ± 0.05, p < 0.0001), and CT-1+hypoxia group (0.31 ± 0.06, p = 0.0005). There was virtually no difference in Pp/Ps between the CT-1+hypoxia and normoxia groups. Mean systemic arterial pressure and heart rate were similar in the four groups (Table 1).
Vasorelaxation response
Administration of CT-1 to rats exposed to ambient air had no effect on either endothelium-dependent or endothelium-independent pulmonary artery vasorelaxation, but endothelium-dependent vasorelaxation was maintained better in the CT-1+hypoxia group than in the hypoxia group. Hypoxic conditions markedly impaired endothelium-dependent vasorelaxation in the precontracted ring segment of the pulmonary artery for ACh concentrations ranging from 10-6 M to 10-5 M. The percentage relaxation for 10-6 M ACh in the hypoxia group was 11.0% ± 3.5%, which was significantly lower than that in the normoxia group (39.9% ± 12.8%, p = 0.003) and that in the CT-1+normoxia group (45.2% ± 24.7%, p = 0.0011). For ACh at 10-5 M, the percentage relaxation in the hypoxia group (17.4% ± 4.8%) was lower than that in the other three groups: normoxia group (59.5% ± 17.4%, p < 0.0001), CT-1+normoxia group (52.8% ± 15.5%, p = 0.0005), and CT-1+hypoxia group (42.3% ± 14.8%, p = 0.0061). There was no appreciable difference in the percentage relaxation among the normoxia, CT-1+normoxia, and CT-1+hypoxia groups (Fig 2).
In contrast, treatment with CT-1 did not affect endothelium-independent vasorelaxation. Chronic hypoxia markedly impaired endothelium-independent vasorelaxation in the precontracted ring segment of the pulmonary artery for SNP concentrations ranging from 10-8 M to 10-6 M. The endothelium-independent vasorelaxation was similar in the CT-1+hypoxia and hypoxia groups for SNP concentrations ranging from 10-9 M to 10-5 M (Fig 3).
Relation between endothelial function and PAP
The development of pulmonary hypertension is prevented by the higher ACh-induced, endothelium-dependent vasodilative response (Fig 4).
Body weight and ventricular hypertrophy
The initial BW was similar in the four groups and rats grew steadily under normoxic conditions. Administration of CT-1 did not affect the change in BW, but hypoxia prevented rats from gaining weight. On the sixth and tenth days the weights of rats in hypoxic groups were similar, and significantly lower than those of rats in normoxic groups (Fig 5).
Administration of CT-1 diminished right ventricular hypertrophy induced by chronic hypoxic conditions. Rats in the normoxia and CT-1+normoxia groups had similar RV/(LV+S) values (0.25 ± 0.03 vs 0.24 ± 0.02, respectively). The RV/(LV+S) values were significantly higher in the hypoxia group (0.42 ± 0.05) than in the normoxia group (p < 0.0001) and in the CT-1+normoxia group (p < 0.0001). Furthermore, the RV/(LV+S) value was also significantly higher in the hypoxia group than in the CT-1+hypoxia group (0.36 ± 0.07, p < 0.0001). Similarly, the RV/BW value was significantly lower in the CT-1+hypoxia group (1.08 ± 0.17 mg/g) than in the hypoxia group (1.29 ± 0.16 mg/g, p < 0.0001; Fig 6).
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Comment
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It is preferable to use NO inhalation against severe pulmonary hypertension after corrective surgery for congenital heart disease [15, 16]. Several investigations, however, have cast doubts on the efficacy of inhaled NO therapy for severe postoperative pulmonary hypertension [17, 18]. Alternative generators of NO with high selectivity to pulmonary arterial pressure or pulmonary vascular resistance are expected because the efficacy of inhaled NO gas varies greatly between individuals. Epoprostenol, a drug for patients with primary pulmonary hypertension, decreases pulmonary vascular resistance and pulmonary blood pressure without concomitant changes in systemic blood pressure in long-term use [19]. However, unlike CT-1, epoprostenol produces no immediate pulmonary depression, and hence epoprostenol may not be appropriate in postoperative pulmonary hypertension. In contrast, CT-1 has a cardioprotective effect [7, 8] in addition to the pulmonary depressor effect, and represents a more promising treatment for patients with pulmonary hypertension before or after congenital cardiac surgery than other vasodilators.
Chronic hypoxia stimulates NO production in endothelial cells. However, NO production is impaired as pulmonary hypertension becomes more severe. In hypoxic pulmonary hypertensive rats, the ACh-induced endothelium-dependent vasodilative response is impaired, and the main contributor to this is the loss of NO activity. Our data clearly indicate that CT-1 inhibits the development of pulmonary hypertension and improves the endothelium-dependent vasodilative response of pulmonary arteries impaired by chronic hypoxia. Preservation of this vasorelaxation probably results in retain of NO production by the pulmonary endothelium. NO may be an intrinsic factor in reducing pulmonary arterial pressure in rats treated with CT-1; however, it is limitation of this model that the NO level was not measured.
Why does CT-1 increase NO and preserve the pulmonary vascular endothelial function? It is possible that vascular endothelial growth factor (VEGF) is involved in the mechanism of the pulmonary depressor effect of CT-1 through NO. A recent study reported that the Janus kinase/signal transducers and activators of transcription-3 pathways through glycoprotein 130, which CT-1 activates, increase the expression of VEGF. Furthermore, CT-1 directly enhances VEGF mRNA expression in a dose-dependent manner in cardiac myocytes [20]. VEGF acts through receptors in the endothelium to enhance the production of NO and prostacyclin, and augments the endothelial function [21, 22]. Hence, the effect of CT-1 against impaired endothelium-dependent vasorelaxation and pulmonary hypertension in chronic hypoxia might implicate VEGFs, although we didn’t examine these factors.
This study indicates that the administration of CT-1 is effective under hypoxic conditions but does not affect in ambient air conditions. Our results suggested that stress stimuli, for instance hypoxia, to pulmonary vessels enhance the effects of CT-1. Pulmonary vascular remodeling associated with chronic hypoxia increases shear stress, which stimulates the basal release of NO [23]. It is possible that the administration of CT-1 under that condition activates further the depressor effect of CT-1 on the pulmonary artery. The method of CT-1 treatment is an important subject, and it is reasonable to assume that CT-1 is not effective in the absence of stress stimuli to pulmonary vessels.
Our results are likely to contrast those from previous studies demonstrating that intravenous administration of CT-1 decreases systemic vascular resistance under normoxic conditions [1, 24]. In those studies, however, the depressor effect of CT-1 on a systemic artery continues for about only 1 hour and thereafter systemic arterial pressure recovers to the basal line. We didn’t measure hemodynamic changes throughout our protocol, and hence we would not have detected transient decreases in systemic arterial pressure that might have occurred at the time of administration in our study. Instead, our measurements of systemic arterial pressure at least 24 hours after the final administration of CT-1 evaluated the chronic rather than the acute effects of CT-1 on systemic and pulmonary arterial pressures.
Our study also contrasts with findings that CT-1 is effective for impairment of endothelium-independent relaxation in endotoxin-induced acute lung injury [3]. The main structural changes caused by endotoxemia are migration of granulocytes and lymphocytes into the interstitium, leading to interstitial edema in the lung [25]. On the other hand, chronic hypoxia causes thickening of the medial and adventitial layers induced by hypertrophy of smooth muscle, hyperplasia of fibroblasts, and deposition of additional matrix; ie, chronic hypoxia induces the changes of organization in the medial and adventitial layers [26, 27]. These differences in structural changes may account for this discrepancy in endothelium-independent vasorelaxation.
Cardiotrophin-1 induces the hypertrophy of cardiac myocytes that occurs during stress stimuli, such as hypoxia or ischemia [7], in the period of compensation [8]. When CT-1 was given by intraperitoneal injection at a dosage of 50 µg/kg per day or more, it induced cardiac hypertrophy in a dose-dependent manner, as was also reported in a previous study [28]. However, our CT-1 dosage of 50 µg/kg per day did not generate cardiac hypertrophy. We injected immature rats with CT-1 once per day for 9 days, but in the previous study [28] mature mice were injected twice per day for 14 days. Our results can be explained by differences in the method of administration of CT-1, animal species, and age between the two studies. We used young (4-week-old) rats for the following two reasons: (1) the purpose of this investigation was treatment of pulmonary hypertension in infants, and (2) the young lung is more sensitive to hypoxia than the adult lung [29]. Thus, treatment with our CT-1 dosage of 50 µg/kg per day is probably effective only for pulmonary hypertension, except for changes of ventricular muscle and systemic arterial pressure.
In conclusion, the present results demonstrate that the administration of CT-1 in a chronic hypoxic model attenuates impairment of endothelium-dependent vasorelaxation and reduces pulmonary arterial pressure, suggesting that CT-1 therapy is effective against pulmonary hypertension induced by chronic hypoxia. Therefore, preoperative administration of CT-1 to patients with cyanotic congenital heart disease may improve the pulmonary condition.
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Acknowledgments
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This work was supported in part by a Grant-in-Aid for Exploratory Research from the Japan Society for the Promotion of Science.
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Top
Abstract
Introduction
p < 0.01 versus hypoxia; 
p < 0.05 versus hypoxia. (CT-1 = cardiotrophin-1; PAP = pulmonary arterial pressure.)
= normoxia (n = 6); 
= CT-1 + normoxia (n = 5); • = hypoxia (n = 6); X = CT-1 + hypoxia (n = 6). (ACh = acetylcholine; CT-1 = cardiotrophin-1.)
