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(Circulation. 2000;102:2269.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Calcineurin Inhibitor Attenuates Left Ventricular Hypertrophy, Leading to Prevention of Heart Failure in Hypertensive Rats
From the Department of Internal Medicine and Therapeutics and Department of Medical Information Science (H.T.), Osaka University Graduate School of Medicine, and Genome Information Research Center, Osaka University, Suita (T. Miwa); and the Department of Pharmacology, Kumamoto University School of Medicine, Kumamoto (H.Y., E.M.), Japan.
Correspondence to Tohru Masuyama, MD, PhD, FACC, Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan. E-mail masuyama{at}medone.med.osaka-u.ac.jp
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role.
Methods and Results—Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg · kg-1 · d-1) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure.
Conclusions—Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.
Key Words: hypertrophy • heart failure • hypertension • calcineurin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Left ventricular (LV) hypertrophy is an adaptive response to volume and pressure overload that works to normalize abnormally elevated wall stress. Prolonged LV hypertrophy may contribute to cardiac dysfunction, however, leading to subsequent cardiovascular events such as congestive heart failure and sudden death. Although LV hypertrophy is a strong predictor of mortality and morbidity in patients with heart disease, it remains unclear how the development of LV hypertrophy is regulated and what facilitates the transition from compensatory to decompensatory hypertrophy.
Over the past decade, a number of experimental studies were performed to identify extracellular factors that facilitate LV hypertrophy. In addition, recent studies clarified the contribution of an intrinsic factor to the development of LV hypertrophy. Molkentin et al1 demonstrated the development of cardiac hypertrophy and eventual heart failure in transgenic mice overexpressing calcium-dependent phosphatase calcineurin or the nuclear transcriptional factor NF-AT3. LV hypertrophy in these mice was blocked by pharmacological inhibition of calcineurin activity, and therefore, the calcineurin transcriptional pathway is likely to play a key role in the development of pressure-overload hypertrophy and heart failure. There is controversy, however, regarding the contribution of calcineurin activation to LV hypertrophy and heart failure due to pressure overload.2 3 4 This is partially because there are few data showing the involvement of calcineurin activation in pressure-overload LV hypertrophy and heart failure models.
Thus, the aim of this study was to explore whether the inhibition of
calcineurin prevents the transition to heart failure in salt-sensitive
hypertensive rats, and if so, to clarify in which developmental stage
of LV hypertrophy calcineurin plays a key role. In this
study, Doppler echocardiography was used to
serially study LV geometry and function. Dahl salt-sensitive rats were
used as a model showing progressive pressure-overload
hypertrophy from the compensated to the decompensated
stage. This model is suitable for our aim, because the rats fed on 8%
NaCl from 7 weeks gradually develop hypertension, followed by
compensatory LV hypertrophy at 13 weeks and in turn by the
transition to diastolic heart failure at 
20
weeks.5
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study conforms to the guiding principles of Osaka University School of Medicine with regard to animal care and to the "Position of the American Heart Association on Research Animal Use" (Circulation. April 1995).
Production of the Model
Laboratory chow containing 0.3% NaCl was continuously fed to
the male Dahl-Iwai salt-sensitive (Dahl S) rats (DIS/Eis, Eisai, Tokyo,
Japan), and they were defined as control rats (n=6). Laboratory chow
containing 0.3% NaCl was fed to weanling Dahl S rats until the diet
was switched to laboratory chow containing 8% NaCl at 7 weeks for the
other rats (n=20). We randomly selected 7 rats out of 20, and these
rats were given FK506 (1 mg ·
kg-1 ·
d-1, courtesy of Fujisawa
Industries Ltd) from 8 to 20 weeks [FK Early (FKE) group]. Another 7
rats were given FK506 (1 mg ·
kg-1 ·
d-1) from 17 to 20 weeks
[FK Late (FKL) group]. The other 6 rats were given placebo [FK(-)
group]. The diet and tap water were given ad libitum throughout the
experiment. Systolic blood pressure and heart rate were
measured every 2 to 5 weeks with a tail-cuff system (BP-98A,
Softron).
Doppler Echo and Hemodynamic Studies
Transthoracic echo Doppler studies were
performed at 7 (just before the 8% NaCl diet was started), 13, 15, 17,
and 20 weeks to determine LV mass, relative wall thickness,
systolic wall stress, endocardial and midwall fractional
shortening, peak early diastolic filling velocity (E
velocity), and peak filling velocity at atrial contraction (A velocity)
in a fashion previously described.5 Soon after Doppler
echo studies, LV catheterization was performed for the
determination of peak positive value of the first derivative of LV
pressure (+dP/dtmax), time constant (
), and
end-diastolic pressure as previously
described.5 The LV myocardial stiffness constant was
obtained from the relation between mean wall stress (
) and the
natural logarithm of the reciprocal of wall thickness [ln(1/H)] by a
previously published method.6
Pathological Studies
After the hemodynamic studies, adequate
anesthesia was achieved, and lung weight and LV mass were
measured as previously described.5 Lung weight and LV mass
were corrected for body weight (lung/body wt and LVMI,
respectively) for quantitative analysis. A part of the LV was
frozen at -80°C for the measurement of hydroxyproline content for
the quantification of mRNA levels. The rest of the LV was immersed in a
cold 4% paraformaldehyde solution for 16 to 24 hours.
The specimens were embedded in paraffin, and 2-µm-thick transverse
sections of the organs were stained with Azan Mallory stain to observe
the degree of fibrosis (Figure 5
).
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Quantitative Reverse-Transcription Polymerase Chain Reaction
Analysis
Quantitative reverse-transcription polymerase chain reaction
analysis was performed with the Prism 7700 Sequence Detector
(Perkin-Elmer Corp) as previously described.7 8 GAPDH and
atrial natriuretic peptide (ANP) mRNAs were measured as
previously described.7 To correct the efficiency of cDNA
synthesis, the amounts of ANP mRNA were divided by the amounts of GAPDH
mRNA.
Calcineurin Phosphatase Assay
Calcineurin activity was measured at the age of 13 weeks in the
tissue of LV myocardium in additional untreated,
FK506-treated, and age-matched control rats (n=3 per group). FK506 was
administered from 8 weeks as in FKE rats. The LV was excised and
immediately stored at -80°C. The frozen rat heart ventricles were
weighed and homogenized with 10 volumes of a
homogenization buffer containing 20 mmol/L
Tris-HCl (pH 7.5), 2 mmol/L EDTA, 2 mmol/L EGTA, 0.1%
Triton X-100, 0.5 mmol/L DTT, and protease inhibitors
(10 µg/mL leupeptin, 1 µg/mL pepstatin A, 1 mmol/L PMSF) with
an Ultra Turrax (IKA-Werk). The homogenate was
centrifuged at 14 000 rpm for 20 minutes at 4°C to obtain
the supernatant as the tissue extract. The protein concentration in the
tissue extract was measured with a BioRad protein assay reagent.
Calcineurin activity was measured using
32P-labeled casein as a substrate. Casein was
phosphorylated by cAMP-dependent protein kinase
(cAMP-kinase) with 0.2 mmol/L [
-32P]ATP
(3000 to 5000 cpm/pmol) overnight. Phosphorylated
casein was heat-treated at 65°C for 5 minutes to remove cAMP-kinase
activity and collected by ammonium sulfate fractionation (0% to 80%)
in the presence of 1 mg/mL BSA. The protein was washed 3 times with
80% ammonium sulfate and dialyzed against a buffer containing 10
mmol/L Tris-HCl (pH 7.5), 10 mmol/L 2-mercaptoethanol, and 10%
(vol/vol) glycerol for 18 hours. The reaction mixture contained, in 25
µL, 50 mmol/L HEPES (pH 7.5), 1 mmol/L DTT, 0.1 mmol/L
MnCl2, 1 mmol/L CaCl2,
1.5 µmol/L calmodulin, 0.2 µmol/L calyculin A
to inhibit protein phosphatases 1 and 2A, and 100 µg/mL
32P-labeled casein. In addition, the phosphatase
activity was measured without CaCl2 and
calmodulin in the presence of 200 µmol/L
trifluoperazine. Calcineurin activity was determined as the activity in
the presence of trifluoperazine without CaCl2 and
calmodulin subtracted from the activity in the presence of
CaCl2 and calmodulin. The reaction
was initiated by the addition of 3 µL of tissue extract. After
incubation at 30°C for 10 minutes, the reaction was terminated by the
addition of 100 µL of 20% TCA and 25 µL of 6 mg/mL BSA. The
samples were centrifuged at 14 000 rpm for 10 minutes at
4°C, and 100 µL of the supernatant was used for counting the amount
of 32P-labeled inorganic phosphate with a liquid
scintillation counter. All assays were performed in duplicate, and the
activity was corrected for the protein concentration. The calcineurin
activity was expressed as a percentage of the mean value of the
age-matched control rats. The calcineurin activity at 13 weeks was
elevated in the untreated rats compared with age-matched normal
controls (182±31% versus 100±25%, respectively), and the elevation
was depressed by the chronic administration of FK506 (101±14%).
Statistical Analysis
Results are expressed as mean±SEM. Data were assessed with
commercially available statistical software (STATVIEW version 4.54,
Abacus Concepts). Differences at specific stages between groups were
assessed by 1-factor ANOVA and Fisher’s test. Two-factor ANOVA for
repeated measures was followed by Fisher’s test for testing serial
changes. A value of P<0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hemodynamics and Heart Failure
None of the control rats developed hypertension or heart failure. Aortic pressure was higher in the FK(-), in FKE, and in FKL rats than in the control rats. (Figure 1
). Aortic
pressure was slightly decreased at 17 and 20 weeks in FKE rats and at
20 weeks in FKL rats compared with the FK(-) rats.
|
P<0.05 vs FK(-) group at same time point.
The lung/body wt increased in the FK(-), rats reflecting congestive
heart failure at 20 weeks (Table 2). It was reduced in FKE rats
but not in FKL rats. LV end-diastolic pressure was elevated
and was prolonged in the FK(-) and FKL rats, but these
abnormalities were not evident in FKE rats. LV systolic
function assessed from endocardial and midwall fractional shortening
was not deteriorated in FK(-), FKE, or FKL rats throughout the
experiment (Table 1 and Figures 2 and 3). The
+dP/dtmax was elevated in FKE rats but reduced in
FKL rats at 20 weeks (Table 2).
End-systolic stress was equivalent among FK(-), FKE, and
control rats but was increased in FKL rats at 20 weeks (Table 2).
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There were no remarkable changes in the Doppler transmitral flow
velocity pattern throughout the experiment in the control group (Table 1
). In contrast, E velocity decreased and A velocity increased
in the FK(-), FKE, and FKL rats at 13 to 17 weeks (Table 1 and
Figures 2 and 3). The FK(-) rats showed increases in E
velocity and in the ratio of E velocity to A velocity (E/A ratio)
(restrictive pattern) at 20 weeks. The administration of FK506 from 8
weeks prevented the transition to the restrictive pattern at 20 weeks;
however, its administration from 17 weeks was not effective.
LV Geometrical and Histological Changes
Posterior wall thickness at end diastole and LVMI
increased at 13, 17, and 20 weeks in the FK(-) rats compared with the
control rats (Tables 1 and 2). The increases were
attenuated, however, by the administration of FK506 from 8 weeks. LV
end-diastolic dimension was smaller in the FK(-) rats than
in the control rats at 13, 17, and 20 weeks. FK506 administration from
8 weeks did not affect LV end-diastolic dimension (Table 1). Changes in LV geometry were not suppressed by FK506
administration after 17 weeks (Tables 1 and 2 and Figures 3 and 4).
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P<0.05 vs FKE group at same time point.
Perivascular and interstitial fibrosis were observed in
FK(-) rats at 20 weeks, particularly in the subendocardial portion
(Figure 5), and did not regress by the
chronic administration of FK506. This observation was confirmed by the
quantitative data of hydroxyproline content (Table 2).
Gene Expression
ANP mRNA level was much higher in FK(-) rats than in the control
rats. FK506 administration from 8 weeks reduced the expression of ANP
mRNA by 41% compared with FK(-) rats. The expression was not reduced,
however, by the treatment starting at 17 weeks (Figure 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The administration of FK506 from the age of 8 weeks attenuated pressure-overload LV hypertrophy and prevented the transition to heart failure in Dahl salt-sensitive rats. If FK506 was administered from the age of 17 weeks, however, the reductive or preventive effect on the development of LV hypertrophy or heart failure was no longer evident. These data indicate that the activation of calcineurin is involved in the development of LV hypertrophy and eventual transition to heart failure in our model and that the involvement may be limited to the initial developmental stage of pressure-overload hypertrophy.
Calcineurin Inhibition From the Initial Stage and LV
Geometry
The administration of FK506 from the age of 8 weeks reduced,
although it did not block, the increase in LVMI. The expression of ANP
mRNA was also reduced in FKE, supporting the idea that calcineurin
inhibition is effective in attenuating LV hypertrophy.
End-systolic stress remained normal in FKE, suggesting that LV
hypertrophy was attenuated to such a degree that it did not
interfere with adaptation to pressure overload. Interestingly,
histological LV fibrosis or LV hydroxyproline content
had not regressed at 20 weeks in FKE rats. Thus, calcineurin activation
is likely to contribute to the development of LV
hypertrophy but little to the progression of LV fibrosis.
The effect on LV hypertrophy was evident from the initial
developmental stage of pressure-overload hypertrophy.
The importance of calcium-dependent phosphatase calcineurin and NF-AT3 was first described by Molkentin et al.1 They studied the effect of pharmacological inhibition of calcineurin activity in transgenic mice to find that the calcineurin transcriptional pathway plays a key role in the development of pressure-induced hypertrophy. Meguro et al2 also observed the attenuation of LV hypertrophy by pharmacological inhibition of calcineurin activity. These reports, however, were followed by in vivo studies3 4 9 showing that the role of calcineurin activation in LV hypertrophy was not as large in conventional models of pressure-overloaded hypertrophy as in the studies by Molkentin et al and Meguro et al. In these studies, administration of cyclosporin A or FK506 did not prevent or attenuate pressure-overload hypertrophy when assessed at 14 to 28 days after banding of the aorta.3 4 9 The discrepancy between our study and these in vivo studies may be explained by the difference in the characteristics of the models of pressure-induced LV hypertrophy. We may speculate that the most important difference is the pattern of increasing blood pressure. In our model, systolic blood pressure gradually rose from 8 to 13 weeks. In contrast, blood pressure rises immediately after the operation in the aortic banding model. We have already demonstrated that the pattern of blood pressure elevation regulates the phenotype of heart failure in rats with genetically identical backgrounds.5 In addition, the sustained change in aortic input impedance affects the geometry of LV hypertrophy in rats with aortic banding.10 These data suggest that the duration and/or type of pressure overload may influence the phenotype of heart failure and geometry of LV hypertrophy. Differences in the duration or type of pressure overload may well account for the difference in the activated neurohumoral factors and/or signal transcriptional pathway; thus, it is not surprising if calcineurin may be related to only a certain phenotype of LV hypertrophy. Further studies are necessary to clarify the difference in the importance of signal transcriptional pathways among various types of pressure-overloaded heart.
Administration of FK506 from 8 weeks did not affect LV hydroxyproline content at 20 weeks, suggesting that the activation of calcineurin is not involved in the development of fibrosis in our model. Because the activation of calcineurin is targeted to myocytes but not to fibroblasts, collagen synthesis in fibroblasts may well be facilitated by other factors, such as angiotensin II, that are independent of the calcineurin transcriptional pathway.11
Calcineurin Inhibition From the Initial Stage and LV
Function
In this study, administration of FK506 from 8 weeks prevented the
increases in lung/body wt ratio and LV end-diastolic
pressure and the transition to a restrictive pattern in the transmitral
flow velocity pattern. To the best of our knowledge, this is the first
report that calcineurin inhibition prevents the transition to heart
failure in a conventional heart failure model induced by pressure
overload.
We have already demonstrated that heart failure develops mainly as a
result of diastolic dysfunction in our model.5
In terms of LV diastolic function, the myocardial stiffness
constant increased in FK(-) rats compared with the normal controls but
was not significantly reduced by the administration of FK506 from 8
weeks. This result is consistent with
histological data showing that the degree of LV
fibrosis was not affected by FK506 administration. Structural
remodeling of extracellular matrix has been implicated in the
alteration of myocardial stiffness.12 13 For example, Thai
et al14 showed that reduction of fibrosis by
administration of angiotensin II type 1 receptor
antagonist was associated with the improvement of
myocardial stiffness constant. Thus, the beneficial effects of the
administration of FK506 cannot be considered to occur through changes
in myocardial stiffness constant or in the degree of fibrosis. Then,
the question arises why heart failure did not develop in FKE regardless
of the unchanged myocardial stiffness constant. The development of LV
hypertrophy was restrained in FKE, and this should account
for the improvement in LV chamber compliance and in the prophylaxis of
LV diastolic failure, because attenuation of LV
hypertrophy decreases LV chamber stiffness constant even
with an unchanged myocardial stiffness constant.15 In
fact, the increase in LV chamber stiffness in FK(-) was reduced in
FKE, as evidenced by the result that LV end-diastolic
pressure was lower in FKE than in FK(-) with similar LV
end-diastolic dimension. Furthermore, was shortened in
FKE compared with FK(-), indicating that LV relaxation was not
deteriorated in FKE despite mild LV hypertrophy. It is
still unknown why FK506 improved LV relaxation. This issue may be
solved in future by studies of the effect of the administration of
FK506 on calcium handling in hypertrophied myocytes.
Calcineurin Inhibition in the Advanced Stage
FK506 and cyclosporin A are not suitable for
prophylactic administration because of their critical side
effects. It would be clinically beneficial, however, if short-term
calcineurin inhibition from the decompensated stage improved LV
function and prevented the transition to heart failure. In our study,
treatment with FK506 from 17 weeks did not shorten the time constant,
decrease the myocardial stiffness constant, decrease lung/body wt and
LV end-diastolic pressure, or decrease LVMI and LV
hydroxyproline content. Thus, the inhibition of calcineurin starting
just before the decompensated stage did not prevent the development of
cardiac remodeling, the deterioration of LV function, or the transition
to heart failure in our model. The activation of calcineurin may not
participate in the transition process to heart failure in our model.
+dP/dtmax was smaller in FKL rats than in FKE
rats. Because +dP/dtmax is a load-dependent
index, the decrease in +dP/dtmax may be partly
explained by increased wall stress in FKL rats. However, the possible
detrimental effect of calcineurin inhibition on decompensated heart has
to be studied in future.
Conclusions
Calcineurin inhibition from the initial developmental stage
of pressure overload attenuated the development of LV
hypertrophy to such a degree that it did not interfere with
adaptation and prevented the transition to heart failure without an
attenuation of LV fibrosis. Calcineurin inhibition from the advanced
developmental stage of pressure overload, however, did not prevent
cardiac remodeling, deterioration of LV function, or the transition to
heart failure in our model. These data suggest that calcineurin
activation is involved in the development of LV hypertrophy
but not in the development of LV fibrosis and that the involvement may
be crucial at the initial stage but negligible just before the
decompensated stage of pressure overload.
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Acknowledgments |
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This work was done with the support of the Ministry of Education and of the Ministry of Health and Welfare of Japan. The authors are grateful to Drs Motoaki Sugawara, Seiichi Hirota, Masami Imakita, and Naoto Minamino for their invaluable comments and to Haruka Kobayashi, Megumi Yoshida, Hisako Nagata, and Mayumi Shinzaki for their excellent technical assistance in the experiment.
Received April 13, 2000; revision received June 2, 2000; accepted June 3, 2000.
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Zhang W, Kowal R, Rusnak F, et al. Failure of
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 B. J Wilkins and J. D Molkentin Calcineurin and cardiac hypertrophy: Where have we been? Where are we going? J. Physiol., May 15, 2002; 541(1): 1 - 8. [Abstract] [Full Text] [PDF]
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 O. F. Bueno, B. J. Wilkins, K. M. Tymitz, B. J. Glascock, T. F. Kimball, J. N. Lorenz, and J. D. Molkentin Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice PNAS, March 19, 2002; (2002) 72647999. [Abstract] [Full Text] [PDF]
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O. F Bueno, E. van Rooij, J. D Molkentin, P. A Doevendans, and L. J De Windt Calcineurin and hypertrophic heart disease: novel insights and remaining questions Cardiovasc Res, March 1, 2002; 53(4): 806 - 821. [Abstract] [Full Text] [PDF]
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W. Zhang Old and new tools to dissect calcineurin's role in pressure-overload cardiac hypertrophy Cardiovasc Res, February 1, 2002; 53(2): 294 - 303. [Abstract] [Full Text] [PDF]
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N. Nishikawa, T. Masuyama, K. Yamamoto, Y. Sakata, T. Mano, T. Miwa, M. Sugawara, and M. Hori Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1539 - 1545. [Abstract] [Full Text] [PDF]
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L. J. De Windt, H. W. Lim, O. F. Bueno, Q. Liang, U. Delling, J. C. Braz, B. J. Glascock, T. F. Kimball, F. del Monte, R. J. Hajjar, et al. Targeted inhibition of calcineurin attenuates cardiac hypertrophy invivo PNAS, March 13, 2001; 98(6): 3322 - 3327. [Abstract] [Full Text] [PDF]
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O. F. Bueno, B. J. Wilkins, K. M. Tymitz, B. J. Glascock, T. F. Kimball, J. N. Lorenz, and J. D. Molkentin Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice PNAS, April 2, 2002; 99(7): 4586 - 4591. [Abstract] [Full Text] [PDF]
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