(Circulation. 2000;102:1996.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Calcineurin Inhibitor Attenuates the Development and Induces the Regression of Cardiac Hypertrophy in Rats With Salt-Sensitive Hypertension
From the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Correspondence to Dr Issei Komuro, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail komuro-tky{at}umin.ac.jp
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Abstract |
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Background—It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.
Methods and Results—In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.
Conclusions—These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.
Key Words: hypertrophy • hemodynamics • hypertension
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Introduction |
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Although cardiac hypertrophy is an adaptive response to various stimuli, prolonged hypertrophy is associated with ischemia, arrhythmia, sudden death, and heart failure.1 2 Therefore, it is very important to understand the underlying mechanism of cardiac hypertrophy and prevent or treat it. Many reports have indicated that intracellular Ca2+ plays an important role in gene expression and growth in a variety of cell types including cardiac myocytes.3 However, it is unknown how Ca2+ regulates these events in cardiomyocytes. Recently, Molkentin et al4 have demonstrated the importance of the Ca2+-dependent phosphatase calcineurin and its downstream transcription factor NF-AT3 in the development of cardiac hypertrophy. Transgenic mice expressing activated calcineurin or NF-AT3 in the heart showed marked cardiac hypertrophy, and some of them progressed to dilated cardiomyopathy with interstitial fibrosis and then congestive heart failure.4 The calcineurin inhibitors cyclosporine A (CsA) and FK506 prevented cardiac hypertrophy in activated calcineurin transgenic mice and humoral factor–induced hypertrophy of cultured cardiomyocytes of neonatal rats.4 In addition, Sussman et al5 reported that several transgenic mouse models that show hypertrophic cardiomyopathy could be treated with CsA. These results suggest that calcineurin plays a pivotal role in the development of cardiac hypertrophy induced by various causes. Although cardiac hypertrophy is induced by a variety of factors such as hemodynamic overload (mechanical stress), genetic factors, and humoral factors, mechanical stress is clinically the most important cause for cardiac hypertrophy.6 7 Sussman et al5 reported that CsA prevented pressure overload–induced cardiac hypertrophy produced by constriction of the abdominal aorta, and Meguro et al8 reported that CsA attenuated cardiac hypertrophy induced by constriction of the transverse aorta. Additionally, we have quite recently reported that FK506 inhibited the pressure overload–induced activation of calcineurin and prevented the pressure overload–induced cardiac hypertrophy and fibrosis produced by constriction of the abdominal aorta.9 In contrast, other groups reported that calcineurin inhibitors did not prevent overload-induced cardiac hypertrophy in spontaneously hypertensive rats (SHR)10 or produced by constriction of the abdominal or transverse aorta.11 12 13 Therefore, it is controversial whether the calcineurin signaling pathway plays a critical role in the development of cardiac hypertrophy induced by hemodynamic overload. Furthermore, it is unknown whether suppression of calcineurin induces the regression of cardiac hypertrophy once cardiac hypertrophy develops.
In this study, we examined the following: (1) whether the calcineurin activity was actually elevated in the hypertrophic heart, (2) how large a dose of the calcineurin inhibitor FK506 was required to suppress the overload-induced elevation of calcineurin activity in the heart, and (3) whether suppression of calcineurin activation in the heart prevented the development or induced the regression of overload-induced cardiac hypertrophy. In the present study, we used Dahl salt-sensitive (DS) rats as the overload-induced cardiac hypertrophy model. The DS rat has unique features as an animal model of cardiac hypertrophy. This model shows the rapid onset of hypertension and develops both pressure overload– and volume overload–induced cardiac hypertrophy only with a high salt diet.14 15 16 In contrast, the Dahl salt-resistant (DR) rat, which is derived from the same colony as the DS rat, remains normotensive with a high salt diet and does not develop cardiac hypertrophy.16
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Methods |
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Animals
Male inbred DS and DR rats were obtained from Nihon Seibutsu Zairyo Inc (Tokyo, Japan). Rats were handled in accordance with the Tokyo University Guide for the Care and Use of Laboratory Animals. Rats were fed a diet containing 0.3% NaCl until the age of 6 weeks, then they were fed an 8% NaCl diet. Systolic blood pressure was measured with an indirect tail-cuff method (BP-98A, Softron). FK506 was injected intramuscularly in DS rats from the age of 6 weeks to 12 weeks or from the age of 12 weeks to 16 weeks. Rats were divided into 4 groups: (1) DR rats, (2) DS rats, (3) DS rats administered a high dose of FK506 (0.1 mg/kg body wt twice daily), and (4) DS rats administered a low dose of FK506 (0.01 mg/kg body wt twice daily) (n=12, each group) (Table 1
). After all rats were
deeply anesthetized by intraperitoneal
injection of sodium pentobarbital (50 mg/kg body wt), rats were killed
and the hearts were subjected to further analysis.
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Calcineurin Enzymatic Assay
The activity of calcineurin in the left ventricle (LV) was
determined as described previously.9 Fresh tissue was
homogenized in hypotonic lysis buffer (50 mmol/L
Tris-HCl, pH 7.5, 0.05% Tween-20, 1 mmol/L EDTA, 1 mmol/L
CaCl2, 1 mmol/L PMSF, 1 µg/mL pepstatin, 1
µg/mL leupeptin, 1 mmol/L DTT), and phosphatase buffer (100
mmol/L MOPS pH 7.0, 0.4 mmol/L CaCl2, 2
mmol/L MnCl2, 10 µg/mL BSA, 100 nmol/L
calmodulin, 500 nmol/L okadaic acid) was added to the
supernatant. The calcineurin substrate GST-RII peptide, which was
phosphorylated by protein kinase A in the presence of
[
-32P]ATP, was incubated with 2 µg of
tissue lysate for 30 minutes at 30°C. Liberated
32P was determined by the Cherenkov method.
Echocardiographic Analysis
At the age of 6 weeks, 12 weeks, and 16 weeks,
transthoracic echocardiographic
analysis was performed repeatedly in the same animal with the
HP Sonos 100 (Hewlett-Packard Co) with a 10-MHz imaging transducer, and
the progress of overload-induced LV hypertrophy was
evaluated as described previously.9
Histological Analysis
For histological analysis, hearts were
fixed by perfusion with 10% formalin. Fixed hearts were embedded in
paraffin, sectioned at 4-µm thickness, and stained with hematoxylin
and eosin or by the van Gieson method. The myocyte cross-sectional
diameter was measured in sections stained with hematoxylin and eosin,
and suitable cross sections were defined as having nearly circular
capillary profiles and nuclei (n=100, each group).17 To
determine the degree of collagen fiber accumulation, we selected 5
fields at random and calculated the ratio of van Gieson–stained
fibrosis area to total myocardium area as described
previously with the software NIH IMAGE (NIH, Research Service
Branch)9 for image analysis.
RNA Analysis
Twenty micrograms of total RNA, extracted from the fresh LV
samples with RNAzol (Tel-text), was separated on a 1.0%
agarose/formaldehyde gel and blotted onto a Hybond-N membrane (Amersham
Co). cDNA was labeled by a random priming method with
[
-32P]dCTP. Hybridized bands were quantified
with NIH IMAGE.
Statistical Analysis
All data are expressed as the mean±SEM. Two-way ANOVA and
Fisher’s exact test for post hoc analysis were carried out for
multiple comparisons among 3 or more groups. A value of
P<0.05 was considered statistically significant.
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Results |
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FK506 Suppresses Pressure Overload–Induced Activation of Calcineurin Without Affecting Hemodynamic Parameters
In DS rats fed the high salt diet from the age of 6 weeks, blood pressure gradually increased and reached the level of
200
mm Hg by the age of 12 weeks (Figure 1A). With the high salt diet for 4 more
weeks, the blood pressure of DS rats increased >220 mm Hg by the
age of 16 weeks (Figure 1B). Treatment with FK506 did not affect
blood pressure in DS rats (Figure 1, A and B). The blood
pressure of DR rats did not significantly change during this period
with the same high salt diet (Figure 1, A and B). Relative
calcineurin activity in the hearts of 12- and 16-week-old DS rats was
significantly higher than that of DR rats of the same age (Table 1
). These results indicate that hemodynamic
overload but not high salt diet itself induces calcineurin activation
in the hearts of DS rats. The work overload–induced elevation of
calcineurin activity was suppressed completely by the high dose of
FK506 and partly by the low dose of FK506 in both 12- and 16-week-old
rats (Table 1).
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12 each).
*P<0.05 vs DR rats of same age.
FK506 Attenuates Development of Cardiac Hypertrophy
Approximately half of DS rats died during the FK506 treatment, and
there was no difference between the 0.1 and 0.01 mg/kg FK506 groups
(Table 1). We dissected all of the dead DS rats and found that
all of the dead animals showed severe pulmonary infection with
empyema. Although the reason is not clear at present, Dahl rats may
be more susceptible to infection than Wistar rats, which were not
infected even with 1 mg/kg FK506.9 The rats that survived
(n=6 to 7) were apparently healthy and used for further
analysis (Table 1). The LV weight (LVW) of 12-week-old
DS rats was significantly higher than that of 12-week-old DR rats
(Figure 2A). Both at high and low doses,
FK506 strongly attenuated the increase in LVW of DS rats (Figure 2A). However, since treatment with FK506 decreased the body
weight (BW) (Figure 2B), there was no significant difference in
the LVW-to-BW ratio (LVW/BW) between DS rats treated with FK506 and
those that were not treated with FK506 (Figure 2C). Because
there was no significant difference in tibial length (TL) among DR
rats, DS rats, and DS rats treated with FK506, we used TL as the
internal control instead of BW.18 19 The LVW-to-TL ratio
(LVW/TL) was significantly higher in DS rats than in DR rats (Figure 2D). Treatment with low and high doses of FK506 significantly
attenuated the overload-induced increase in LVW/TL (Figure 2D).
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Echocardiographic analysis revealed that the
thickness of both the interventricular septum (IVS) and
left ventricular posterior wall (PW) was larger in DS rats
than in DR rats (Table 2). Chronic
treatment with either dose of FK506 attenuated the increment of wall
thickness without affecting cardiac function (Table 2).
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Microscopic analysis revealed that hemodynamic
overload for 6 weeks markedly increased the cross-sectional diameter of
cardiac myocytes (Figure 3A). Treatment
with both high and low doses of FK506 from 6 weeks to 12 weeks
attenuated the increase of the cross-sectional diameter of cardiac
myocytes (Figure 3A). Moreover, hemodynamic
overload induced marked perivascular fibrosis in the heart (Figure 3B). The hemodynamic overload–induced fibrosis
was completely inhibited by treatment with the high dose of FK506 and
partly by treatment with the low dose of FK506 (Figure 3B).
There was no significant difference in the number of inflammatory cells
in hearts between treated and untreated rats.
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Treatment with High Dose of FK506 Induces Regression of
Cardiac Hypertrophy
LVW was significantly larger in DS rats than in DR rats at the age
of 16 weeks (Figure 4A). Treatment with
the high dose of FK506 for 4 weeks significantly attenuated the
increase in LVW in DS rats (Figure 4A). DS rats lost BW from the
age of 12 weeks to 16 weeks irrespective of the treatment as reported
previously,16 and the BW of 16-week-old DS rats was
significantly smaller than that of DR rats (Figure 4B). Both the
LVW/BW and LVW/TL were significantly larger in DS rats than in DR rats,
and treatment with the high dose of FK506 but not with the low dose of
FK506 significantly attenuated the increase in the LVW/BW as well as
the LVW/TL (Figure 4, C and D). Moreover, the LVW/TL of
16-week-old DS rats that were treated with the high dose of FK506 was
significantly less than that of untreated 12-week-old DS rats (Figure 4D), suggesting that the FK506 treatment induced regression of
cardiac hypertrophy.
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Echocardiographic analysis revealed that
hemodynamic overload for an additional 4 weeks (weeks
12 to 16) was associated with further increase of the thickness of both
IVS and PW (Table 3). At the high dose but not low dose FK506
treatment not only attenuated the development but also induced the
regression of cardiac hypertrophy without any impairment of
cardiac function (Table 3). The thickness of IVS and PW was
decreased in 16-week-old DS rats by treatment with the FK506 as
compared with that of untreated 12-week-old DS rats (Table 3).
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Microscopic analysis revealed that the cross-sectional diameter
of cardiac myocytes was significantly larger in DS rats than in DR rats
at the age of 16 weeks (Figure 5A). At
the high dose but not at the low dose, FK506 induced regression of
hypertrophy of cardiac myocytes in DS rats (Figure 5A). The cardiomyocyte diameter of treated
16-week-old DS rats was smaller than that of nontreated 12-week-old DS
rats. Additionally, hemodynamic overload for a further
4 weeks markedly induced progression of the perivascular fibrosis in
the hearts of 16-week-old DS rats (Figure 5B). Treatment with
FK506 from the age of 12 weeks to 16 weeks attenuated the development
of the overload-induced fibrosis in a dose-dependent manner (Figure 5B).
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Calcineurin Is Involved in Load-Induced Reprogramming of Gene
Expression
Induction of fetal-type genes is a genetic response to
hemodynamic overload.6 We thus examined
whether calcineurin was involved in gene expression during
overload-induced cardiac hypertrophy.
Hemodynamic overload for 6 weeks upregulated fetal
genes such as atrial natriuretic peptide (ANP), brain
natriuretic peptide (BNP), and skeletal -actin genes in
the heart (Figure 6, A and B). In
contrast, the sarcoplasmic reticulum Ca2+-ATPase
(SERCA2) gene was downregulated in the hearts of DS rats, as
previously reported20 (Figure 6, A and B).
Treatment with FK506 from 6 weeks to 12 weeks dose-dependently
inhibited the upregulation of the BNP gene and the
downregulation of the SERCA2 gene (Figure 6, A and
B). The upregulation of ANP and skeletal -actin genes was
not affected by treatment with FK506 (Figure 6, A and B).
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Discussion |
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In this study, treatment with the high dose of FK506 for 6 weeks abolished the overload-induced activation of calcineurin and attenuated the development of cardiac hypertrophy in 12-week-old DS rats without change of hemodynamic parameters (Figures 1
, 2, and 3 and
Table 1). In addition, treatment with the high dose of FK506
from the age of 12 weeks to 16 weeks induced significant regression of
cardiac hypertrophy (Figures 4 and 5).
Furthermore, we demonstrated that treatment with the high dose of FK506
inhibited cardiac fibrosis (Figures 3 and 5). Treatment
with the low dose of FK506, which was almost the same as the dose used
in a clinical setting, suppressed the overload-induced elevation of
calcineurin activity by 40% and attenuated the development of
cardiac hypertrophy and fibrosis in 12-week-old DS rats
(Figures 2 and 3). At the low dose, however, FK506 did
not induce the regression of cardiac hypertrophy at the age
of 16 weeks (Figures 4 and 5). There are controversial reports on the role of calcineurin in overload-induced cardiac hypertrophy.5 8 9 10 11 12 13 Although the reason of the discrepancy is not clear at present, it may come from the model of hemodynamic overload. It has been reported that CsA does not prevent overload-induced cardiac hypertrophy, as in the case of constriction of the ascending or transverse aorta12 13 or of SHR.8 In this study, we used DS rats as the overload-induced cardiac hypertrophy model. DS rats have several unique features as a model of hypertensive cardiac hypertrophy. They show rapid onset of hypertension without variation among animals and develop both pressure-overload– and volume-overload–induced cardiac hypertrophy only when fed a high salt diet.14 15 16 DS rats show not only salt-sensitive hypertension but also hypertriglyceridemia and hyperinsulinemia,21 22 suggesting that DS rats have some features similar to human hypertension. It has also been reported that expression levels of interleukin-1ß and monocyte chemoattractant protein-1 are increased in the left ventricle of DS rats.23 Cytokines have been reported to play an important role in the development of cardiac hypertrophy and failure.6 24 25 Although there was no significant difference in the degree of macrophage infiltration between FK506-treated DS rats and nontreated rats in our study (data not shown), it is possible that FK506 may inhibit the development of cardiac hypertrophy by suppressing the production of cytokines.
Although overload-induced activation of calcineurin was
completely inhibited by treatment with the high dose of FK506, the
development of cardiac hypertrophy was only partly
inhibited. These results suggest that signaling pathways other than the
calcineurin pathway are also involved in the development of cardiac
hypertrophy in this model. Mende et al26
demonstrated that cardiac hypertrophy and dilated
cardiomyopathy induced by constitutive activation
of Gq, which activates the protein kinase C signaling
pathway, is partially inhibited by treatment with CsA. These results
suggest that there might be also some cross-talk between the
calcineurin pathway and the protein kinase pathways.
It is difficult to evaluate cardiac hypertrophy when
BW changes markedly. When BW decreases as the result of exercise,
excess thyroid hormone, diet, and senescence, LVW does not usually
change concomitantly with BW.27 Actually, when DR rats
were treated with FK506, the LVW did not decrease despite the marked
decrease in BW (data not shown). It has been reported that the tibial
growth curve is independent of the presence or absence of diseases and
of changes in BW.18 19 Therefore, TL may be a better
internal control than BW to assess relative size of organs including
the heart. Echocardiographic analysis revealed
that treatment with FK506 attenuated or induced regression of cardiac
hypertrophy (Table 2). Microscopic analysis
also showed that the cross-sectional diameter of cardiac myocytes and
perivascular fibrosis were significantly increased in DS rats and that
treatment with FK506 attenuated overload-induced enlargement of cardiac
myocytes and fibrosis (Figures 3 and 5). In particular,
the high dose of FK506 treatment completely prevented the development
of hemodynamic overload–induced perivascular fibrosis
(Figures 3B and 5B). Although weight loss may have
independently modified LV mass,28 29 all these results
suggest that activation of calcineurin is involved in load-induced
cardiac hypertrophy.
FK506 inhibited overload-induced upregulation of the
BNP gene and downregulation of the SERCA2 gene
but did not alter the expression of ANP or skeletal
-actin genes (Figure 6). In our previous study with an
abdominal aortic banding model, however, an increase in ANP expression
was also inhibited by FK506 treatment.9 In our
previous study, we treated the rats of abdominal aortic constriction
with 1 mg/kg per day of FK506, and this treatment completely prevented
pressure overload–induced calcineurin activation and cardiac
hypertrophy.9 Because DS rats were susceptible
to infection with unknown reason, we treated DS rats with 0.1 mg or
0.01 mg/kg twice daily of FK506 in the present study, and this
treatment inhibited load-induced calcineurin activation in a
dose-dependent manner and attenuated load-induced cardiac
hypertrophy. These observations suggest that complete
inhibition of load-induced calcineurin activation is required to
inhibit load-induced upregulation of the ANP gene. Quite
recently, Taigen et al30 demonstrated that target
inhibition of calcineurin by expressing noncompetitive peptide
inhibitors cain and A-kinase anchoring protein, by using
adenoviral-mediated gene transfer, attenuated agonist-induced
calcineurin activity, cardiomyocyte
hypertrophy, and upregulation of the ANP gene.
These noncompetitive peptide inhibitors may be useful to
elucidate the role of calcineurin in load-induced cardiac
hypertrophy while avoiding severe side effects of
calcineurin inhibitors.
It has been reported that NF-AT3 activates transcription of some cardiac genes in concert with cardiac-enriched transcription factor GATA4.4 31 Additionally, it was reported that activation of calcineurin selectively upregulates slow-fiber–specific genes in skeletal myocytes through NF-AT3-MEF2 association32 and that calcineurin is involved in skeletal muscle hypertrophy by activating GATA2 and NF-ATc.33 34 35 It has been reported that MEF2 plays an important role in gene regulation also in the heart36 and that NF-ATc plays a vital role in the morphogenesis of the cardiac valves and septum during heart development.37 38 Furthermore, it has recently been reported that intracellular Ca2+ homeostasis regulates calcineurin activity and plays a vital role in cardiac development or development of dilated cardiomyopathy.39 40 Mesaeli et al39 demonstrated that calreticulin, which is a ubiquitous Ca2+-binding protein and located in the endoplasmic reticulum lumen, plays a role in cardiac development as a component of the calcineurin-NF-AT3–GATA4 transcription pathway. Sussman et al40 reported that alteration of intracellular calcium handling induced calcineurin activation, altered sarcomeric structure, and induced dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. From these results and observations, calcineurin may be involved in the regulation of many cardiac genes through activation of the NF-AT family including NF-AT3 and NF-ATc and may be involved in cardiac hypertrophy and development.
In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.01 or 0.1 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Treatment with 0.1 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by FK506.
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Acknowledgments |
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This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture and by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Drug ADR Relief, R&D Promotion, and Product Review of Japan.
Received March 23, 2000; revision received May 22, 2000; accepted May 22, 2000.
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