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1 Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, 2 Gene Experiment Center, Institute of Applied Biochemistry, and 3 Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pressure overload,
such as hypertension, to the heart causes pathological cardiac
hypertrophy, whereas chronic exercise causes physiological cardiac
hypertrophy, which is defined as athletic heart. There are differences
in cardiac properties between these two types of hypertrophy. We
investigated whether mRNA expression of various cardiovascular
regulating factors differs in rat hearts that are physiologically and
pathologically hypertrophied, because we hypothesized that these two
types of cardiac hypertrophy induce different molecular phenotypes. We
used the spontaneously hypertensive rat (SHR group; 19 wk old) as a
model of pathological hypertrophy and swim-trained rats (trained group;
19 wk old, swim training for 15 wk) as a model of physiological
hypertrophy. We also used sedentary Wistar-Kyoto rats as the control
group (19 wk old). Left ventricular mass index for body weight was
significantly higher in SHR and trained groups than in the control
group. Expression of brain natriuretic peptide, angiotensin-converting
enzyme, and endothelin-1 mRNA in the heart was significantly higher in
the SHR group than in control and trained groups. Expression of
adrenomedullin mRNA in the heart was significantly lower in the trained
group than in control and SHR groups. Expression of
1-adrenergic receptor mRNA in the heart was
significantly higher in SHR and trained groups than in the control
group. Expression of 1-adrenergic receptor kinase mRNA,
which inhibits 1-adrenergic receptor activity, in the
heart was markedly higher in the SHR group than in control and trained
groups. We demonstrated for the first time that the manner of mRNA
expression of various cardiovascular regulating factors in the heart
differs between physiological and pathological cardiac hypertrophy.
cardiovascular regulating factor; athletic heart; spontaneously hypertensive rat; swim training; hypertension
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CHRONIC EXERCISE TRAINING causes cardiac hypertrophy, which is defined as athletic heart (7, 26). The athletic heart is a physiological cardiac hypertrophy, which is an induced beneficial adaptive response of the cardiovascular system, i.e., decreased resting and submaximal heart rates and increased filling time and venous return (1, 22, 28, 35). Together, these adaptations can help the myocardium satisfy the increased demands of exercise while maintaining or enhancing normal function (1, 22, 28, 35). Although it has been considered that exercise training-induced cardiac hypertrophy is partly caused by the increase in mechanical load by repeated bouts of exercise (28), the precise mechanisms are not known.
Hypertension and cardiac valvular disease induce pathological cardiac hypertrophy caused by pressure overload (24, 28). Pathological cardiac hypertrophy is a compensatory adaptation to an increase in workload of the heart (24). Pathological cardiac hypertrophy reduces cardiac function in the left ventricle (28). Furthermore, it has been reported that the progression of pathological cardiac hypertrophy results in heart failure (24, 27). Thus there are differences in cardiac properties between pathological and physiological cardiac hypertrophy (athletic heart).
Recently, it has been reported that some cardiovascular regulating
factors participate in pathological cardiac hypertrophy (27). Recent in vivo studies have suggested that ANG II is
a growth factor for pathological cardiac hypertrophy (16,
40). ANG II is converted from ANG I by angiotensin-converting
enzyme (ACE). It has also been reported that ANG II plays an important role in the pathogenesis of heart failure (25).
Furthermore, increased expression of ACE has been reported in the
failing heart (25). Endothelin-1 (ET-1) also induces
cardiac hypertrophy (11, 36). We previously reported that
the tissue level of ET-1 is markedly increased in the failing heart of
rats with congestive heart failure due to myocardial infarction
(30, 31). Activation of the myocardial
1-adrenergic pathway also induces cardiac hypertrophy (27, 42). Furthermore, pressure overload hypertrophy and
failing heart cause an increase in mRNA expression of brain natriuretic peptide (BNP) and a shift of isozyme from 
- to -myosin heavy chain (MHC) (10, 27, 29). It has been reported that
adrenomedullin, which is produced in cardiac myocytes, inhibits
hypertrophy of cardiac myocytes in vitro (5, 37).
Therefore, it is considered that various cardiovascular regulating
factors, such as ANG II, ET-1, BNP, adrenomedullin,
1-adrenergic pathway, and MHC, participate in the
development of pathological cardiac hypertrophy. Although the
athletic heart exhibits physiological cardiac hypertrophy, it is
unknown whether the various cardiovascular regulating factors participate in the development of athletic heart induced by chronic exercise training.
Because there are differences in cardiac properties between pathological and physiological cardiac hypertrophy, we hypothesized that the manner of mRNA expression of various cardiovascular regulating factors in the rat heart differs between these two types of hypertrophy. Therefore, we investigated whether the mRNA expression of various cardiovascular regulating factors differs between physiological cardiac hypertrophy (athletic heart) and pathological cardiac hypertrophy. In the present study, we used the spontaneously hypertensive rat (SHR; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk, 5 days/wk) as a model of physiological hypertrophy. We also determined whether hemodynamic features differ in the trained and SHR groups.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals and protocol.
Experimental protocols were approved by the Committee on Animal
Research at the University of Tsukuba. Male 4-wk-old Wistar-Kyoto (WKY)
rats and SHR were obtained from Charles River Japan (Yokohama, Japan)
and cared for according to the Guiding Principles for the Care
and Use of Animals, based on the Helsinki Declaration of 1964. The
rats were maintained on a 12:12-h light-dark cycle and received food
and water ad libitum. Eight WKY rats were exercised by swimming for 5 days/wk (trained group) in a tank of water at 30-32°C with a
surface area of 1,960 cm2 and a depth of 50 cm. The rats
swam for 5 min/day for the first 2 days, and then the swim time was
increased gradually over the 2-wk period from 5 to 75 min/day.
Thereafter, the trained group continued swim training for 13 wk.
Therefore, the trained group received 15 wk of swim training. Eight SHR
(SHR group) and seven WKY rats (control group) remained confined to
their cages but were handled daily. After swim training for 15 wk, the
body weight and hemodynamic parameters of the animals were measured,
and the heart was removed, weighed, and frozen in liquid nitrogen.
Heart samples were stored at 
80°C for determination of the
expression levels of mRNA of various cardiovascular regulating factors
by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Control rats and SHR were killed at the same time point as the trained
rats: all were 19 wk old.
Hemodynamic measurement and tissue sampling.
On the day of the experiment, hemodynamic parameters were measured in
anesthetized rats, as described previously (21, 29-31, 38,
39), with minor modifications. The rats were anesthetized with
thiobutabarbital (50 mg/kg body wt ip). After the rats were fully
sedated, arterial blood pressure and heart rate (HR) were measured via
a cannula in the carotid artery with a pressure transducer (model
SCK-590, Gould) connected to a polygraph system (amplifier: model
AP-601G, Nihon Kohden, Tokyo, Japan; tachometer: model AT-601G, Nihon
Kohden; thermal-pen recorder: model WT-687G, Nihon Kohden). Arterial
blood pressure and HR were monitored and recorded continuously. Stroke
volume (SV) was measured by the thermodilution technique using a
Cardiotherm 500 cardiac output computer (Columbus Instruments, OH)
equipped with a small animal interface (3, 18). The
thermistor microprobe catheter (Fr-1; Columbus Instruments) was
inserted into the right carotid artery and advanced to the aortic arch. A catheter placed in the left jugular vein was advanced to the right
ventricle for rapid bolus injection of 200 µl (plus catheter dead
space) of cold saline. The saline solution was injected with a Hamilton
constant-rate syringe to ensure rapid and repeatable injections of the
saline indicator solution. The cardiac output measurement was repeated
five times. Cardiac output was measured again when the aortic blood
temperature of the rat was 
36°C, and the arterial blood pressure
returned to the baseline value. Catheter placement was verified by
postmortem examination. Body temperature of the rat was maintained at
37°C by using a small animal warmer (model BWT-100, Bio Research
Center, Nagoya, Japan). SV was determined by dividing cardiac output by
the HR. After hemodynamic measurement, the whole heart was rapidly
excised and washed thoroughly with cold saline to remove contaminating
blood; then the left ventricle was separated from the right ventricle and atria. The left ventricle was weighed, frozen in liquid nitrogen, and stored at 80°C until extraction of total RNA.
Use of RT-PCR to determine levels of mRNA expression in heart.
Expression of BNP mRNA, ACE mRNA, ET-1 mRNA, adrenomedullin mRNA,
1-adrenergic receptor mRNA, 1-adrenergic
receptor kinase mRNA, muscarinic M2 receptor mRNA, and MHC
mRNA in the left ventricle was analyzed by RT-PCR. Expression of
-actin mRNA was determined as an internal control. Semiquantitative
RT-PCR was performed according to the method we described previously
(9, 13, 20, 29, 38, 39).
1-adrenergic receptor
(19), 1-adrenergic receptor kinase
(2), muscarinic M2 receptor (8),
MHC (17), and -actin (23). The
sequences of the oligonucleotides were as follows:
5'-TAATCTGTCGCCGCTGGGAGG-3' (sense) and 5'-GAGCTGGGGAAAGAAGAGCCG-3' (antisense) for BNP, 5'-GTTCGTGGAGGAGTATGACCG-3' (sense) and
5'-CCGTTGAGCTTGGCGATCTTG-3' (antisense) for ACE,
5'-TCTTCTCTCTGCTGTTTGTG-3' (sense) and
5'-TTAGTTTTCTTCCCTCCACC-3' (antisense) for ET-1,
5'-GGTTCGCTCGCCGTTCTCG-3' (sense) and
5'-GCCACCCGCACCTATAACCT-3' (antisense) for adrenomedullin,
5'-CGCTCACCAACCTCTTCATCATGTCC-3' (sense) and
5'-CAGCACTTGGGGTCGTTGTAGCAGC-3' (antisense) for
1-adrenergic receptor, 5'-AGATGGCCGACCTGGAGGC-3' (sense)
and 5'-GGAGTCAAAGATCTCCCG-3' (antisense) for
1-adrenergic receptor kinase,
5'-CACGAAACCTCTGACCTACCC-3' (sense) and 5'-TCTGACCCGACGACCCAACTA-3'
(antisense) for muscarinic M2 receptor,
5'-GCAGACCATCAAGGACCT-3' (sense) and 5'-GTTGGCCTGTTCCTCCGCC-3' (antisense) for MHC, 5'-GAAGATCCTGACCGAGCGTG-3' (sense) and
5'-CGTACTCCTGCTTGCTGATCC-3' (antisense) for -actin. PCR was carried
out using a PCR thermal cycler (model TP-3000, Takara) according to the
method described by us previously (9, 13, 20, 29, 38, 39).
The cycle profile included denaturation for 15 s at 94°C,
annealing for each suitable time at each suitable temperature, and
extension for each suitable time at 72°C. The annealing time and
temperature were set as follows: 15 s at 70°C for BNP, 15 s
at 69°C for ACE, 15 s at 54°C for ET-1, 15 s at 69°C
for adrenomedullin, 30 s at 66°C for 1-adrenergic
receptor, 15 s at 55°C for 1-adrenergic receptor
kinase, 15 s at 71°C for muscarinic M2 receptor,
15 s at 63°C for MHC, and 15 s at 72°C for -actin. The
extension time was set as follows: 45 s for BNP, ACE, ET-1,
1-adrenergic receptor kinase, and MHC and 60 s for
adrenomedullin, 1-adrenergic receptor, muscarinic
M2 receptor, and -actin. The reaction cycles of PCR were
performed in the range that demonstrated a linear correlation between
the amount of cDNA and the yield of PCR products. After PCR in MHC,
distinction between - and -MHC was achieved by digestion of 12.5 µl of the PCR mixture with 0.8 U of MseI in a standard reaction buffer at 37°C for 4 h (29). This yielded
fragments of 310 bp for -MHC and 275 + 53 bp for -MHC. The
PCR products were of the expected size, as shown by 1.5% agarose gel
electrophoresis for BNP, ACE, ET-1, adrenomedullin,
1-adrenergic receptor, 1-adrenergic receptor kinase, muscarinic M2 receptor, and -actin and
2.0% agarose gel electrophoresis for MHC. In addition, the specificity of the amplified sequences was confirmed by restriction enzyme analysis
and DNA sequencing. The DNA sequence of each amplicon was perfectly
matched to each published sequence.
Semiquantitative analysis of PCR products.
The amplified PCR products were electrophoresed on 1.5% agarose gels,
stained with ethidium bromide, visualized by an ultraviolet transilluminator, and photographed according to the method described previously (9, 13, 20, 29, 38, 39). The photographs were
scanned by CanoScan 600 (Canon, Tokyo, Japan), and quantification was
performed by a computer with MacBAS software (Fuji Film, Tokyo, Japan)
according to the method described previously (9, 13, 20, 29, 38,
39). The cDNAs for the verification of the semiquantitative PCR
analysis were prepared from each gene PCR product of rat cDNA. Each PCR
product was purified, quantified, and used as a positive-control cDNA.
We performed semiquantitative PCR analysis to evaluate the expression
levels of BNP mRNA, ACE mRNA, ET-1 mRNA, adrenomedullin mRNA,
1-adrenergic receptor mRNA, 1-adrenergic
receptor kinase mRNA, muscarinic M2 receptor mRNA, MHC
mRNA, and -actin mRNA. To demonstrate that our semiquantitative PCR
strategy was valid, serial dilutions of each positive-control cDNA were
amplified by PCR and quantified by a scanner.
Statistical analysis. Values are means ± SE. Statistical analysis was carried out by analysis of variance followed by Scheffé's F test for multiple comparisons. P < 0.05 was accepted as significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamic parameters in control, trained, and SHR groups.
Body weight was significantly lower in the trained group than in the
control and SHR groups (Table 1). Left
ventricular mass index for body weight was higher in the SHR and
trained groups than in the control group (Table 1). Resting HR was
lower in the trained group than in the control and SHR groups and
significantly higher in the SHR group than in the control group (Table
1). Systolic and diastolic blood pressure were significantly higher in
the SHR group than in the control and trained groups (Table 1). SV was
lower in the SHR group than in the control and trained groups (Table
1). Pressure-rate product, which is an index of cardiac workload, was
higher in the SHR group than in the control and trained groups (Table
1). These results suggest that the heart of trained rats exhibited
physiological cardiac hypertrophy (athletic heart), and the heart of
SHR exhibited pathological cardiac hypertrophy.
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mRNA expression of cardiovascular regulating factors in heart.
Expression of BNP mRNA, ACE mRNA, and ET-1 mRNA in the heart was
significantly higher in the SHR group than in the control and trained
groups (Fig. 1). There was no significant
difference between the control and trained groups in expression of BNP
mRNA, ACE mRNA, and ET-1 mRNA (Fig. 1). Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in
the control and SHR groups (Fig. 2).
Expression of 1-adrenergic receptor mRNA in the heart
was significantly higher in the SHR and trained groups than in the
control group (Fig. 3A). There was no significant difference between the SHR and trained groups in
expression of 1-adrenergic receptor mRNA (Fig.
3A). Expression of 1-adrenergic receptor
kinase mRNA, which inhibits 1-adrenergic receptor
activity, in the heart was markedly higher in the SHR group than in the
control and trained groups (Fig. 3B). There was no
significant difference between the control and trained groups in
expression of 1-adrenergic receptor kinase (Fig.
3B). There were no significant differences among the three
groups in expression of muscarinic M2 receptor mRNA (Fig.
3C). Expression of -MHC mRNA in the heart was
significantly higher in the trained group than in the SHR group (Fig.
4A). There were no significant differences among the three groups in expression of -MHC mRNA (Fig.
4B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differed between physiological cardiac hypertrophy, which is induced by chronic exercise, and pathological cardiac hypertrophy, which is induced by hypertension. In the present study, the hearts of SHR and trained rats developed cardiac hypertrophy, as evidenced by an increase in left ventricular mass index for body weight. Trained rats received 15 wk of swim training, which caused enhancement of cardiac function, i.e., a decrease in resting HR and pressure-rate product and an increase in SV. SHR developed cardiac hypertrophy by hypertension and showed a decline in cardiac function, i.e., increase in resting HR and pressure-rate product and decrease in SV. Therefore, these results suggest that trained rats exhibited physiological cardiac hypertrophy (athletic heart) and SHR exhibited pathological cardiac hypertrophy.
The present study revealed that expression of BNP mRNA, ACE mRNA, and ET-1 mRNA in the heart was significantly higher in the SHR group than in the control and trained groups. It has been reported that BNP is involved in pathological cardiac hypertrophy (10). Furthermore, pathological cardiac hypertrophy is partly induced by humoral cardiovascular regulating factors such as ANG II (16, 40), which is converted from ANG I by ACE, and ET-1 (11, 36). These humoral cardiovascular regulating factors activate mitogen-activated protein kinase by the activation of GTP-binding (Gq) protein (4, 41, 43), thereby resulting in cardiac myocyte hypertrophy (6, 27). Furthermore, cardiac hypertrophy and contractile dysfunction have been reported in Gq-overexpressing mice (6). Therefore, it is considered that Gq overactivation induces heart failure. In the present study, the mRNA expression of ACE and ET-1, which activate Gq protein, in the heart was increased in the SHR group. Taken together, the development of pathological cardiac hypertrophy in SHR in the present study may be partly caused by ANG II- and ET-1-induced activation of Gq protein. In the present study, the expression of ACE and ET-1 mRNA in the heart was not altered by 15 wk of swim training. Therefore, it is likely that activation of the Gq-signaling pathway by ANG II or ET-1 may not mainly participate in the development of physiological cardiac hypertrophy. Furthermore, the expression of BNP mRNA in the heart was not altered by exercise training. Therefore, it is possible that physiological cardiac hypertrophy (athletic heart) is induced by other mechanisms.
Cardiac myocytes, as well as vascular endothelial cells, produce adrenomedullin (5). It has been reported that adrenomedullin inhibits hypertrophy of cardiac myocytes in vitro (37). In the present study, the expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in the control and SHR groups. Therefore, the decrease in expression of adrenomedullin mRNA in the trained heart in this study may have accelerated the development of physiological cardiac hypertrophy in the trained rats. It is possible that a decrease in expression of myocardial adrenomedullin partly participates in development of the athletic heart.
The present study revealed that mRNA expression of
1-adrenergic receptor, which is a receptor in the signal
transduction pathway in sympathetic nerve stimulation, in the heart was
significantly higher in the SHR and trained groups than in the control
group. However, mRNA expression of 1-adrenergic receptor
kinase, which inhibits activation of the signal transduction system
downstream of the 1-adrenergic receptor by
desensitization of the 1-adrenergic receptor, in the
heart was markedly higher in the SHR group than in the control and
trained groups. These findings suggest that in the heart of trained
rats the signal transduction system downstream of
1-adrenergic receptor was activated, whereas in SHR the
signal transduction system downstream of the
1-adrenergic receptor was inactivated. Therefore, it is
considered that the signal transduction system of the
1-adrenergic receptor in the heart differs between the
athletic heart (physiological cardiac hypertrophy) and pathological cardiac hypertrophy. Sympathetic nervous system activity has been implicated in development of cardiac hypertrophy (27). An
in vivo study also indicated that stimulation of -adrenergic
receptors leads to development of myocardial hypertrophy independent of hemodynamic effects (42). Furthermore, Ji et al.
(12) reported that -adrenergic blockade prevented
exercise training-induced cardiac hypertrophy. On the basis of results
from past studies plus the present results, it is considered that
1-adrenergic system activity participates in development
of the athletic heart (physiological cardiac hypertrophy). In the
present study, there were no significant differences among the three
groups in mRNA expression of muscarinic M2 receptor, which
binds acetylcholine released from parasympathetic nerve endings.
In the present study, expression of -MHC mRNA in the heart was
significantly higher in the trained group than in the SHR group. We
also demonstrated that expression of -MHC mRNA in the heart was
slightly increased in the SHR group. It has been reported that
hypertension in rats results in a shift of myosin isozymes from the
predominant V1 to the V3 pattern and that
physical training by swimming in rats results in an increase in the
percentage of V1 myosin isozyme in cardiac myosin
(34). These observations are consistent with our findings.
Therefore, these results suggest that the myosin isozyme differs
between the athletic heart (physiological cardiac hypertrophy) and
pathological cardiac hypertrophy. Furthermore, we suspect that
Ca2+-ATPase activity accelerates in the athletic heart and
is attenuated in pathological cardiac hypertrophy, because the
V1 myosin isozyme accelerates Ca2+-ATPase
activity, whereas the V3 myosin isozyme attenuates
Ca2+-ATPase activity.
The mechanism underlying the differences in the mRNAs measured between the athletic heart and pathological cardiac hypertrophy remains to be elucidated. However, the following mechanism is possible. Trained rats (athletic heart) induce tachycardia only during exercise, whereas SHR (pathological cardiac hypertrophy) sustain tachycardia and hypertension at all times. The difference in periods of tachycardia and hypertension between the trained rats and SHR might cause a difference in workload on the heart. Therefore, it is possible that a difference in the persistence in the workload on the heart between the trained rats and SHR is one of the causal factors for the difference in mRNA expressions in these two types of hypertrophy.
In conclusion, we have demonstrated that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between pathological and physiological cardiac hypertrophy (athletic heart). The present study also demonstrated that hemodynamic features in the heart differed between pathological and physiological cardiac hypertrophy. We speculate that the different alterations in the molecular phenotypes between the athletic heart (physiological cardiac hypertrophy) and pathological cardiac hypertrophy are among the causal factors in the differences in hemodynamic features (e.g., SV and cardiac diastolic function) and the prognosis of cardiac hypertrophy (predisposition to heart disease or failure).
Perspectives
It is generally accepted that there are differences in cardiac function between physiological and pathological cardiac hypertrophy (24, 26, 28). The present study demonstrated a new molecular finding that the manner of mRNA expression of various cardiovascular regulating factors in the heart differed between physiological and pathological cardiac hypertrophy. These findings showed that a different molecular mechanism of formation of cardiac hypertrophy is possible between these two types of cardiac hypertrophy. Further studies to precisely reveal molecular features of physiological and pathological cardiac hypertrophy are needed, because these further studies will provide important findings on molecular and cellular mechanism of formation of physiological and pathological cardiac hypertrophy. In this regard, it is of great interest and of importance to study 1) whether the change in mRNA expression between physiological and pathological cardiac hypertrophy contributes to a change in expression of protein level or mature substance level in these hearts, 2) whether there is a difference in the signaling pathway mediated through these substances between these two types of cardiac hypertrophy, and 3) how the pharmacological action of these proteins or substances on the cardiac myocytes differently alters in these two types of cardiac hypertrophy. The present study demonstrated different molecular phenotypes between physiological and pathological cardiac hypertrophy. Therefore, the present study raised an important question, which should be solved by further studies: Is there a difference in the molecular mechanism of formation of cardiac hypertrophy between physiological and pathological cardiac hypertrophy?| |
ACKNOWLEDGEMENTS |
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We thank Dr. Wendy Gray for editing the English language of our manuscript.
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FOOTNOTES |
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This study was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan (00006781, 11557047, 12470147); and by a grant from the Miyauchi Project of the Center for Tsukuba Advanced Research Alliance at the University of Tsukuba.
Address for reprint requests and other correspondence: T. Miyauchi, Cardiovascular Div., Dept. of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan (E-mail: t-miyauc{at}md.tsukuba.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 April 2001; accepted in final form 27 July 2001.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Adams, TD,
Yanowitz FG,
Fisher AG,
Ridges JD,
Lovell K,
and
Pryor TA.
Noninvasive evaluation of exercise training in college-age men.
Circulation
64:
958-965,
1981
2.
Arriza, JL,
Dawson TM,
Simerly RB,
Martin LJ,
Caron MG,
Snyder SH,
and
Lefkowitz RJ.
The G-protein-coupled receptor kinases ARK1 and ARK2 are widely distributed at synapses in rat brain.
J Neurosci
12:
4045-4055,
1992[Abstract].
3.
Champion, HC,
and
Kadowitz PJ.
D-[Ala2]endomorphin 2 and endomorphin 2 have nitric oxide-dependent vasodilator activity in rats.
Am J Physiol Heart Circ Physiol
274:
H1690-H1697,
1998
4.
Clerk, A,
Michael A,
and
Sugden PH.
Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G protein-coupled receptor agonists endothelin-1 and phenylephrine: a role in cardiac myocyte hypertrophy?
J Cell Biol
142:
523-535,
1998
5.
Cormier-Regard, S,
Nguyen SV,
and
Claycomb WC.
Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes.
J Biol Chem
273:
17787-17792,
1998
6.
Dorn, GW II,
and
Brown JH.
Gq signaling in cardiac adaptation and maladaptation.
Trends Cardiovasc Med
9:
26-34,
1999[Web of Science][Medline].
7.
Fagard, RH.
Impact of different sports and training on cardiac structure and function.
Cardiol Clin
15:
397-412,
1997[Medline].
8.
Gocayne, J,
Robinson DA,
FitzGerald MG,
Chung FZ,
Kerlavage AR,
Lentes KU,
Lai J,
Wang CD,
Fraser CM,
and
Venter JC.
Primary structure of rat cardiac -adrenergic and muscarinic cholinergic receptors obtained by automated DNA sequence analysis: further evidence for a multigene family.
Proc Natl Acad Sci USA
84:
8296-8300,
1987
9.
Iemitsu, M,
Miyauchi T,
Maeda S,
Yuki K,
Kobayashi T,
Kumagai Y,
Shimojo N,
Yamaguchi I,
and
Matsuda M.
Intense exercise causes decrease in expression of both endothelial NO synthase and tissue NOx level in hearts.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R951-R959,
2000
10.
Iso, T,
Arai M,
Wada A,
Kogure K,
Suzuki T,
and
Nagai R.
Humoral factor(s) produced by pressure overload enhance cardiac hypertrophy and natriuretic peptide expression.
Am J Physiol Heart Circ Physiol
273:
H113-H118,
1997
11.
Ito, H,
Hiroe M,
Hirata Y,
Fujisaki H,
Adachi S,
Akimoto H,
Ohta Y,
and
Marumo F.
Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload.
Circulation
89:
2198-2203,
1994
12.
Ji, LL,
Stratman FW,
and
Lardy HA.
Effects of 1- and 1 + 2-antagonists on training-induced myocardial hypertrophy and enzyme adaptation.
Biochem Pharmacol
36:
3411-3417,
1987[Web of Science][Medline].
13.
Kobayashi, T,
Miyauchi T,
Sakai S,
Kobayashi M,
Yamaguchi I,
Goto K,
and
Sugishita Y.
Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart.
Am J Physiol Heart Circ Physiol
276:
H1197-H1206,
1999
14.
Koike, G,
Krieger JE,
Jacob HJ,
Mukoyama M,
Pratt RE,
and
Dzau VJ.
Angiotensin-converting enzyme and genetic hypertension: cloning of rat cDNAs and characterization of the enzyme.
Biochem Biophys Res Commun
198:
380-386,
1994[Web of Science][Medline].
15.
Kojima, M,
Minamino N,
Kangawa K,
and
Matsuo H.
Cloning and sequence analysis of cDNA encoding a precursor for rat brain natriuretic peptide.
Biochem Biophys Res Commun
159:
1420-1426,
1989[Web of Science][Medline].
16.
Kojima, M,
Shiojima I,
Yamazaki T,
Komuro I,
Zou Y,
Wang Y,
Mizuno T,
Ueki K,
Tobe K,
Kadowaki T,
Nagai R,
and
Yazaki Y.
Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro.
Circulation
89:
2204-2211,
1994
17.
Kraft, R,
Bravo-Zehnder M,
Taylor DA,
and
Leinwand LA.
Complete nucleotide sequence of full-length cDNA for rat -cardiac myosin heavy chain.
Nucleic Acids Res
17:
7529-7530,
1989
18.
Kreisman, NR,
Gauthier-Lewis ML,
Conklin SG,
Voss NF,
and
Barbee RW.
Cardiac output and regional hemodynamics during recurrent seizures in rats.
Brain Res
626:
295-302,
1993[Web of Science][Medline].
19.
Machida, CA,
Bunzow JR,
Searles RP,
Van Tol H,
Tester B,
Neve KA,
Teal P,
Nipper V,
and
Civelli O.
Molecular cloning and expression of the rat 1-adrenergic receptor gene.
J Biol Chem
265:
12960-12965,
1990
20.
Maeda, S,
Miyauchi T,
Sakai S,
Kobayashi T,
Iemitsu M,
Goto K,
Sugishita Y,
and
Matsuda M.
Prolonged exercise causes an increase in endothelin-1 production in the heart in rats.
Am J Physiol Heart Circ Physiol
275:
H2105-H2112,
1998
21.
Miyauchi, T,
Yorikane R,
Sakai S,
Sakurai T,
Okada M,
Nishikibe M,
Yano M,
Yamaguchi I,
Sugishita Y,
and
Goto K.
Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.
Circ Res
73:
887-897,
1993
22.
Möckel, M,
and
Störk T.
Diastolic function in various forms of left ventricular hypertrophy: contribution of active Doppler stress echo.
Int J Sports Med
17:
S184-S190,
1996.
23.
Nudel, U,
Zakut R,
Shani M,
Neuman S,
Levy Z,
and
Yaffe D.
The nucleotide sequence of the rat cytoplasmic -actin gene.
Nucleic Acids Res
11:
1759-1771,
1983
24.
Panidis, IP,
Kotler MN,
Ren JF,
Mintz GS,
Ross J,
and
Kalman P.
Development and regression of left ventricular hypertrophy.
J Am Coll Cardiol
3:
1309-1320,
1984[Abstract].
25.
Pieruzzi, F,
Abassi ZA,
and
Keiser HR.
Expression of renin-angiotensin system components in the heart, kidneys, and lungs of rats with experimental heart failure.
Circulation
92:
3105-3112,
1995
26.
Raskoff, WJ,
Goldman S,
and
Cohn K.
The "athletic heart." Prevalence and physiological significance of left ventricular enlargement in distance runners.
JAMA
236:
158-162,
1976
27.
Reddy, DS.
Cellular and molecular biology of cardiac hypertrophy.
Curr Sci
72:
13-30,
1997.
28.
Richey, PA,
and
Brown SP.
Pathological versus physiological left ventricular hypertrophy: a review.
J Sports Sci
16:
129-141,
1998[Web of Science][Medline].
29.
Sakai, S,
Miyauchi T,
and
Yamaguchi I.
Long-term endothelin receptor antagonist administration improves alterations in expression of various cardiac genes in failing myocardium of rats with heart failure.
Circulation
101:
2849-2853,
2000
30.
Sakai, S,
Miyauchi T,
Kobayashi M,
Yamaguchi I,
Goto K,
and
Sugishita Y.
Inhibition of myocardial endothelin pathway improves long-term survival in heart failure.
Nature
384:
353-355,
1996[Medline].
31.
Sakai, S,
Miyauchi T,
Sakurai T,
Kasuya Y,
Ihara M,
Yamaguchi I,
Goto K,
and
Sugishita Y.
Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heart.
Circulation
93:
1214-1222,
1996
32.
Sakata, J,
Shimokubo T,
Kitamura K,
Nakamura S,
Kangawa K,
Matsuo H,
and
Eto T.
Molecular cloning and biological activities of rat adrenomedullin, a hypotensive peptide.
Biochem Biophys Res Commun
195:
921-927,
1993[Web of Science][Medline].
33.
Sakurai, T,
Yanagisawa M,
Inoue A,
Ryan US,
Kimura S,
Mitsui Y,
Goto K,
and
Masaki T.
cDNA cloning, sequence analysis and tissue distribution of rat preproendothelin-1 mRNA.
Biochem Biophys Res Commun
175:
44-47,
1991[Web of Science][Medline].
34.
Scheuer, J,
Malhotra A,
Hirsch C,
Capasso J,
and
Schaible TF.
Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy in rats.
J Clin Invest
70:
1300-1305,
1982.
35.
Shapiro, LM,
and
Smith RG.
Effect of training on left ventricular structure and function: an echocardiographic study.
Br Heart J
50:
534-539,
1983
36.
Shubeita, HE,
McDonough PM,
Harris AN,
Knowlton KU,
Glembotski CC,
Brown JH,
and
Chien KR.
Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes: a paracrine mechanism for myocardial cell hypertrophy.
J Biol Chem
265:
20555-20562,
1990
37.
Tsuruda, T,
Kato J,
Kitamura K,
Kuwasako K,
Imamura T,
Koiwaya Y,
Tsuji T,
Kangawa K,
and
Eto T.
Adrenomedullin: a possible autocrine or paracrine inhibitor of hypertrophy of cardiomyocytes.
Hypertension
31:
505-510,
1998
38.
Ueno, M,
Miyauchi T,
Sakai S,
Kobayashi T,
Goto K,
and
Yamaguchi I.
Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors.
Am J Physiol Regulatory Integrative Comp Physiol
277:
R1321-R1330,
1999
39.
Yamauchi-Kono, R,
Miyauchi T,
Hoshina T,
Kobayashi T,
Aihara H,
Sakai S,
Yabana H,
Goto K,
Sugishita Y,
and
Murata S.
Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: increase in endothelin-1 production in the heart and beneficial effect of endothelin A receptor antagonist on survival and cardiac function.
Circulation
99:
2171-2176,
1999
40.
Yamazaki, T,
Komuro I,
Kudoh S,
Zou Y,
Shiojima I,
Mizuno T,
Takano H,
Hiroi Y,
Ueki K,
Tobe K,
Kadowaki T,
Nagai R,
and
Yazaki Y.
Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy.
Circ Res
77:
258-265,
1995
41.
Yamazaki, T,
Komuro I,
Kudoh S,
Zou Y,
Shiojima I,
Hiroi Y,
Mizuno T,
Maemura K,
Kurihara H,
Aikawa R,
Takano H,
and
Yazaki Y.
Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy.
J Biol Chem
271:
3221-3228,
1996
42.
Zierhut, W,
and
Zimmer H-G.
Significance of myocardial - and -adrenoceptors in catecholamine-induced cardiac hypertrophy.
Circ Res
65:
1417-1425,
1989
43.
Zou, Y,
Komuro I,
Yamazaki T,
Aikawa R,
Kudoh S,
Shiojima I,
Hiroi Y,
Mizuno T,
and
Yazaki Y.
Protein kinase C, but not tyrosine kinases or Ras, plays a critical role in angiotensin II-induced activation of Raf-1 kinase and extracellular signal-regulated protein kinases in cardiac myocytes.
J Biol Chem
271:
33592-33597,
1996
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