(Circulation. 1999;100:2449.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Calcineurin Plays a Critical Role in Pressure Overload–Induced Cardiac Hypertrophy
From the Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine (M.S., D.H., E.T., Y.Z., T.O., H.U., S.K., Y.Y., I.K.), and the Tokyo Metropolitan Institute of Medical Science (F.S), Tokyo, Japan.
Correspondence to Issei Komuro, MD, PhD, 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—Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload–induced cardiac hypertrophy.
Methods and Results—Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload–induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment.
Conclusions—The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.
Key Words: hypertrophy • pressure • genes • calcineurin
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Introduction |
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Although cardiac hypertrophy is a beneficial adaptive response of the heart to an increased workload, hypertrophic heart often leads to dilated cardiomyopathy and eventually causes congestive heart failure after sustained overload.1 Moreover, recent epidemiological studies revealed that cardiac hypertrophy is an independent risk factor for ischemic heart disease, arrhythmia, and sudden death.2 Therefore, it is even more important to determine the mechanism of the development of cardiac hypertrophy.
Many lines of evidence have suggested that although cardiac hypertrophy can be induced by a variety of factors, such as hemodynamic overload (mechanical stress), genetic factors, and humoral factors, mechanical stress is the most important cause of cardiac hypertrophy.3 Mechanical stress on cardiac myocytes induces various hypertrophic responses, including activation of protein kinases, reprogramming of gene expression, and an increase in protein synthesis.3 4 Among intracellular signaling molecules, protein kinases such as protein kinase C, tyrosine kinases, and the mitogen-activated protein kinase family have been reported to play an important role in the development of cardiac hypertrophy.5 6 7 8 9
Although many reports have suggested that intracellular Ca2+ plays an important role in gene expression and growth in a variety of cell types, including cardiac myocytes,10 it is unknown how Ca2+ regulates these events in cardiomyocytes. Recently, Molkentin et al11 reported that the Ca2+-dependent phosphatase calcineurin plays a vital role in the development of cardiac hypertrophy through activation of NF-AT3, a member of a transcription factor family initially discovered in immune T cells.12 Both transgenic mice expressing activated calcineurin and NF-AT3 showed marked cardiac hypertrophy, and some of them progressed to dilated cardiomyopathy with interstitial fibrosis and showed congestive heart failure.11 The calcineurin inhibitors cyclosporin A (CsA) and FK506 prevented cardiac hypertrophy of activated calcineurin transgenic mice and humoral factor–induced hypertrophy of cultured cardiomyocytes of neonatal rats.11 In addition, Sussman et al13 also reported that several transgenic mice models that show hypertrophic cardiomyopathy can be treated with CsA. These results suggest that calcineurin plays a vital role in the development of cardiac hypertrophy induced by various causes. In the present study, using a pressure-overload model of abdominal aortic constriction, we examined whether calcineurin is also involved in load-induced cardiac hypertrophy.
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Methods |
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Rat Preparation
Male Wistar rats (8 weeks old; 230 to 250 g) obtained from Nihon Seibutsu Zairyo Inc (Tokyo, Japan) were divided into 3 groups: (1) sham-operated rats, (2) pressure-overloaded rats without FK506, and (3) pressure-overloaded rats with FK506 (n=14, each group). Pressure overload was produced by constriction of the abdominal aorta as described previously.14 Briefly, the rats were anesthetized with an injection of a cocktail of ketamine HCl 100 mg/kg and xylazine 5 mg/kg IP. The abdominal aorta was constricted above the renal arteries by a 4-0 silk suture tied around both the aorta and a blunted 22-gauge needle, which was then pulled out. FK506, 1 mg · kg body wt-1 · d-1 IM, was administered from 3 days before operation through 3 weeks after. After rats were killed, hearts were removed, rinsed in PBS buffer, and separated into the right and left ventricles (LV). Total RNA (20 µg), extracted from the 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 the random priming method with [
-32P]dCTP. Hybridized bands were quantified
with NIH IMAGE software (NIH, Research Service Branch).
Hemodynamic Measurements In Vivo
To measure short- and long-term hemodynamic
effects of aortic constriction, the right carotid artery was cannulated
with a 24-gauge polyethylene catheter. The transducer (Baxter, model MP
5100) was connected to a Mac Laboratory system (model 400/s, AD
Instruments), and the blood pressure and heart rate were measured.
Calcineurin Enzymatic Assay
The activity of calcineurin in lysates of LV samples was
determined as described previously.15 Tissue was
homogenized in 50 µL of 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, and 1 mmol/L DTT) and subjected to
1 round of freeze and thaw. After cell debris had been removed by
centrifugation, 50 µL of 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, and 500 nmol/L okadic acid) was added to the
supernatant. A calcineurin substrate, GST-RII peptide, which was fixed
to glutathione-cellulose beads, was first
phosphorylated by protein kinase A in the presence of
[
-32P]ATP. Phosphorylated
RII peptide was incubated with 2 µg of tissue lysate for 30 minutes
at 30°C. Reactions were stopped, and the liberated
32P was determined by the Cherenkov method.
Echocardiographic Analysis
At 20 days after operation, transthoracic
echocardiographic analysis was performed with
HP sonos 100 (Hewlett-Packard Co) with a 10-MHz imaging transducer as
described previously.16 Rats were weakly
anesthetized with an injection of a cocktail of
ketamine HCl 50 mg/kg and xylazine 2.5 mg/kg IP. When the rats
partially recovered from anesthesia, M-mode images of the
LV were recorded.
Histological Analysis
For histological analysis, hearts were
fixed with 10% formamide by perfusion fixation. Fixed hearts were
embedded in paraffin, sectioned at 4-µm thickness, and stained by the
van Gieson method for collagen. To determine the degree of collagen
fiber accumulation, we selected 5 fields randomly and calculated the
ratio of van Gieson–stained fibrosis area to total myocardial area as
described previously with the image analysis software NIH
IMAGE.16
Statistical Analysis
All data are expressed as the mean±SEM. Multiple comparisons
among 
3 groups were carried out by 2-way ANOVA and Fisher’s exact
test for post hoc analysis. A value of P<0.05 was
considered statistically significant.
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Results |
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Calcineurin Inhibitor FK506 Suppresses Pressure Overload–Induced Activation of Calcineurin Without Affecting Hemodynamic Parameters
Blood pressure monitored at the right carotid arteries was increased from 74.6±5.7 to 145.5±6.5 mm Hg soon after aortic constriction, and the elevation of blood pressure was also observed at 3 weeks after the operation (144.8±2.7 mm Hg, Figure 1A
). FK506, 1 mg/kg body wt IM, was
injected every day from 3 days before constriction of the abdominal
aorta up to 3 weeks after. All rats survived throughout the treatment
protocol, and hemodynamic parameters, such
as the blood pressure and heart rate, were not affected by this
treatment (Figure 1A). To examine whether pressure overload
changes the calcineurin activity, we performed calcineurin enzymatic
assays.16 Relative calcineurin activity in hearts from
control rats (no operation nor injection of FK506) was 684±54 cpm/µg
protein (Figure 1B). Although sham operation did not change the
activity of calcineurin (674±14 cpm/µg), pressure overload for 2
hours significantly increased the relative calcineurin activity to
910±22 cpm/µg in the heart (Figure 1B). Treatment with FK506
completely suppressed the elevation of the calcineurin activity
(500±31 cpm/µg) (Figure 1B). Pressure overload–induced
elevation of the calcineurin activity was still observed at 3 weeks
after operation (975±37 cpm/µg), and chronic treatment with FK506
also completely inhibited the elevation (631±48 cpm/µg) (Figure 1B).
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FK506 Prevents Pressure Overload–Induced Cardiac
Hypertrophy
Pressure overload for 3 weeks induced marked cardiac
hypertrophy (Figure 2A).
Chronic treatment with FK506 completely prevented the development of
pressure overload–induced cardiac hypertrophy (Figure 2A). There was no significant difference in body weight among
sham-operated rats and banded rats with or without the FK506 treatment
(Figure 3). Pressure overload for 3 weeks
significantly increased the ratio of LV weight to body weight (banded
rats, 3.07±0.14 mg/g versus sham, 2.12±0.04 mg/g) (Figure 3).
Treatment with FK506 completely prevented the pressure
overload–induced increase in the ratio of LV weight to body weight
(banded rats treated with FK506, 2.18±0.03 mg/g) (Figure 3).
Echocardiographic analysis revealed that
pressure overload increased the thickness of both the
interventricular septum (IVS) (banded, 1.94±0.17 mm
versus sham, 1.32±0.04 mm) and the LV posterior wall (PW)
(banded, 1.90±0.16 mm versus sham, 1.28±0.05 mm) (Figure 4). The FK506 treatment completely
inhibited the increment of wall thickness without affecting cardiac
function (IVS, 1.23±0.07 mm; PW, 1.13±0.02 mm) (Figure 4).
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Cardiac fibrosis is often observed in hypertrophic
hearts.17 Microscopic analysis revealed
that pressure overload for 3 weeks markedly induced perivascular
fibrosis in the heart (
12% of total area) (Figure 2B
and 2C). Treatment with FK506 also inhibited the pressure overload–induced
fibrosis (Figure 2B and 2C).
Calcineurin Is Involved in Pressure Overload–Induced Reprogramming
of Gene Expression
Induction of immediate-early-response genes and fetal genes is a
genetic response to hemodynamic overload.3
The activation of calcineurin has been reported to upregulate the brain
natriuretic peptide (BNP) gene through activation of
NF-AT3.11 We thus examined whether calcineurin is involved
in gene expression during load-induced cardiac hypertrophy.
Pressure overload upregulated the expression of
immediate-early-response genes, such as c-fos,
c-jun, and BNP genes (Figure 5A and 5C), and fetal genes, such as
skeletal -actin and atrial natriuretic peptide (ANP)
genes (Figure 5B and 5D), in the heart as previously
reported.3 In contrast, the sarcoplasmic reticulum
Ca2+-ATPase (SERCA2) gene was downregulated in
the heart by pressure overload (Figure 5B and 5D).18 Treatment with FK506 inhibited the pressure
overload–induced regulation of some of these genes. Upregulation of
c-fos, BNP, and ANP genes and downregulation of the SERCA2
gene were fully inhibited by the FK506 treatment, whereas upregulation
of c-jun and skeletal -actin genes was not affected by
the treatment (Figure 5).
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Discussion |
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This study demonstrated that calcineurin is activated by pressure overload in the heart and that the activated calcineurin plays a critical role in the development of load-induced cardiac hypertrophy. While we were preparing the manuscript, several groups reported controversial results.13 19 20 21 Sussman et al13 reported that 20 mg/kg CsA treatment prevents acute pressure overload–induced cardiac hypertrophy. Meguro et al19 reported that CsA could attenuate but not prevent LV hypertrophy, and Luo et al20 and Zhang et al21 reported that calcineurin inhibitors had no effects on load-induced cardiac hypertrophy in the same pressure-overload model as ours. Although the reason for the discrepancy is not known at present, it may come from the dose and the route of administration of the calcineurin inhibitors. Luo et al injected 20 to 40 mg/kg CsA SC or 2 to 4 mg/kg FK506 IV, and quite a high percentage of banded rats (30% to 90%) died with these treatments.20 The treatment by Zhang et al21 was similar to that by Luo et al, and mortality was also very high (33% to 67%). Sussman et al13 also reported that all rats of the banded group were dead within 1 week after 20 mg/kg CsA treatment. Systemic administration of CsA or FK506 dose-dependently induces many side effects, such as infection, renal failure, diabetes mellitus, and hypertension.22 Because our preliminary experiments revealed that injection of FK506 10 mg/kg body wt IP or IM killed many rats and caused serious side effects, such as cachexia and infection, and that injection of 1 mg/kg FK506 IM was enough to inhibit load-induced activation of calcineurin in the heart without any side effects, we injected 1 mg/kg FK506 every day from 3 days before operation up to 3 weeks after in the present study. In this dose, no rats were dead until at least 3 weeks after operation, and no decrease in body weight or infection was observed in our treatment (n=7 each group) (Figure 3
). From this point of view, the dose and
the route of administration of calcineurin inhibitors might
be quite critical to evaluate their role in the development of
load-induced cardiac hypertrophy.
Treatment with FK506 fully inhibited pressure overload–induced cardiac
hypertrophy and fibrosis (Figures 2, 3, and 4). FK506, a macrolide compound isolated from Streptomyces
tsukubaensis, has potent immunosuppressive
properties.23 FK506 is 10 to 100 times more potent
than CsA.24 FK506 binds to FK506 binding protein (FKBP),
and the FK506/FKBP complex inhibits calcineurin.24 In
cardiomyocytes, it has been reported that FK506 binds to
FKBP and opens the ryanodine receptor, resulting in an increase in
intracellular calcium concentration.24 25 26 Therefore, it
is possible that the FK506 modulated the ryanodine receptor in this
study. However, the following observations suggest that treatment with
FK506 suppressed the development of cardiac hypertrophy
through inhibition of the calcineurin activity. The FK506
treatment suppressed the load-induced elevation of calcineurin
activity, and our preliminary results show a good correlation between
the calcineurin activity and the degree of cardiac
hypertrophy (Figure 1B, unpublished observations).
In addition, CsA, which binds to another protein, cyclophilin, showed
similar inhibitory effects on the development of
load-induced cardiac hypertrophy (unpublished
observations).
Many lines of evidence have suggested that vasoactive peptides, including angiotensin II (Ang II) and endothelin-1, play an important role in mechanical stress–induced cardiac hypertrophy.3 27 28 It has also been reported that Ang II plays a critical role in this pressure-overload rat model of abdominal aortic constriction3 and that Ang II–induced hypertrophy of cultured cardiomyocytes is inhibited by CsA.11 Therefore, it is conceivable that FK506 effectively prevented pressure overload–induced cardiac hypertrophy in this model by inhibiting Ang II–induced calcineurin activation in the heart. It has been reported that CsA is not effective in preventing load-induced cardiac hypertrophy, which is induced by constriction of the ascending or transverse aorta.29 30 Because Ang II is not involved in the pressure-overload model of ascending or transverse aortic constriction,31 it is possible that CsA was not effective in preventing load-induced hypertrophy in that model.29 30 Whether calcineurin is involved in the development of load-induced cardiac hypertrophy may depend on the model of hemodynamic overload. Although it remains unclear how activated calcineurin induces cardiac hypertrophy, activation of NF-AT3 may play an important role.11 In analogy with activated T cells,12 NF-AT3 may upregulate cytokines of the interleukin-6 family, such as cardiotrophin-1 and leukemia inhibitory factor, which are strong inducers of cardiomyocyte hypertrophy.32 The mechanism of induction of cardiac hypertrophy and fibrosis by activated calcineurin awaits further investigation.
FK506 inhibited load-induced expression of some of the
immediate-early-response genes and fetal genes, but upregulation of
c-jun and skeletal -actin genes was not affected by FK506
(Figure 5). These results suggest that calcineurin is involved
in pressure overload–induced expression of some specific genes but not
of all genes and that FK506 inhibited load-induced gene expression by
suppressing calcineurin activation in the heart without affecting
hemodynamic load. Molkentin et al11
reported that NF-AT3 activates transcription of some cardiac
genes in concert with the cardiac enriched transcription factor GATA4.
Recently, it was reported that activation of calcineurin selectively
upregulates slow-fiber–specific genes in skeletal myocytes through
NF-AT3-MEF2 association.33 Because MEF2 plays an important
role in gene regulation in the heart as well,34
calcineurin may be involved in the regulation of many cardiac genes
through activation of NF-AT3.
Molkentin et al,11 using the transgenic mouse strategy, first demonstrated that activated calcineurin could induce cardiac hypertrophy. Sussman et al13 next showed that calcineurin may be involved in the generation of hypertrophic cardiomyopathy. The present study suggests that calcineurin plays a critical role in the development of the load-induced cardiac hypertrophy, which is most often observed clinically. In addition, Lim et al35 recently demonstrated that calcineurin is activated in the heart in human heart failure. Because of severe side effects, it may not be realistic to use calcineurin inhibitors in the present form to prevent the development of cardiac hypertrophy. However, because the possibility exists that inhibition of calcineurin may prevent not only the development of cardiac hypertrophy but also that of heart failure, it should be worthwhile to develop novel calcineurin inhibitors.
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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 of Japan and by the Program for Promotion of Fundamental Studies in Health Science of the Organization for Drug ADR Relief, R&D Promotion, and Product Review of Japan.
Received March 24, 1999; revision received July 2, 1999; accepted July 13, 1999.
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M. U Braun, P. Szalai, R. H Strasser, and M. M Borst Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymes Cardiovasc Res, September 1, 2003; 59(3): 658 - 667. [Abstract] [Full Text] [PDF]
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C. L. Antos, T. A. McKinsey, M. Dreitz, L. M. Hollingsworth, C.-L. Zhang, K. Schreiber, H. Rindt, R. J. Gorczynski, and E. N. Olson Dose-dependent Blockade to Cardiomyocyte Hypertrophy by Histone Deacetylase Inhibitors J. Biol. Chem., August 1, 2003; 278(31): 28930 - 28937. [Abstract] [Full Text] [PDF]
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L. M. Semeniuk, D. L. Severson, A. J. Kryski, S. L. Swirp, J. D. Molkentin, and H. J. Duff Time-dependent systolic and diastolic function in mice overexpressing calcineurin Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H425 - H430. [Abstract] [Full Text] [PDF]
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J. Pan, B. Hinzmann, W. Yan, F. Wu, J. Morser, and Q. Wu Genomic Structures of the Human and Murine Corin Genes and Functional GATA Elements in Their Promoters J. Biol. Chem., October 4, 2002; 277(41): 38390 - 38398. [Abstract] [Full Text] [PDF]
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M. U Braun, P. LaRosee, S. Schon, M. M Borst, and R. H Strasser Differential regulation of cardiac protein kinase C isozyme expression after aortic banding in rat Cardiovasc Res, October 1, 2002; 56(1): 52 - 63. [Abstract] [Full Text] [PDF]
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Y. Wang, G. W. De Keulenaer, E. O. Weinberg, S. Muangman, A. Gualberto, K. T. Landschulz, T. G. Turi, J. F. Thompson, and R. T. Lee Direct biomechanical induction of endogenous calcineurin inhibitor Down Syndrome Critical Region-1 in cardiac myocytes Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H533 - H539. [Abstract] [Full Text] [PDF]
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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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R. S. Williams Calcineurin Signaling in Human Cardiac Hypertrophy Circulation, May 14, 2002; 105(19): 2242 - 2243. [Full Text] [PDF]
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O. Ritter, S. Hack, K. Schuh, N. Rothlein, A. Perrot, K. J. Osterziel, H. D. Schulte, and L. Neyses Calcineurin in Human Heart Hypertrophy Circulation, May 14, 2002; 105(19): 2265 - 2269. [Abstract] [Full Text] [PDF]
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G. Chu, A. N. Carr, K. B. Young, J.W. Lester, A. Yatani, A. Sanbe, M. C. Colbert, S. M. Schwartz, K. F. Frank, P. D. Lampe, et al. Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure Cardiovasc Res, April 1, 2002; 54(1): 105 - 116. [Abstract] [Full Text] [PDF]
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J. A. Hill, B. Rothermel, K.-D. Yoo, B. Cabuay, E. Demetroulis, R. M. Weiss, W. Kutschke, R. Bassel-Duby, and R. S. Williams Targeted Inhibition of Calcineurin in Pressure-overload Cardiac Hypertrophy. PRESERVATION OF SYSTOLIC FUNCTION J. Biol. Chem., March 15, 2002; 277(12): 10251 - 10255. [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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Y. Zou, Y. Hiroi, H. Uozumi, E. Takimoto, H. Toko, W. Zhu, S. Kudoh, M. Mizukami, M. Shimoyama, F. Shibasaki, et al. Calcineurin Plays a Critical Role in the Development of Pressure Overload-Induced Cardiac Hypertrophy Circulation, July 3, 2001; 104(1): 97 - 101. [Abstract] [Full Text] [PDF]
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Y. Zou, A. Yao, W. Zhu, S. Kudoh, Y. Hiroi, M. Shimoyama, H. Uozumi, O. Kohmoto, T. Takahashi, F. Shibasaki, et al. Isoproterenol Activates Extracellular Signal-Regulated Protein Kinases in Cardiomyocytes Through Calcineurin Circulation, July 3, 2001; 104(1): 102 - 108. [Abstract] [Full Text] [PDF]
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B. A. Rothermel, T. A. McKinsey, R. B. Vega, R. L. Nicol, P. Mammen, J. Yang, C. L. Antos, J. M. Shelton, R. Bassel-Duby, E. N. Olson, et al. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo PNAS, March 13, 2001; 98(6): 3328 - 3333. [Abstract] [Full Text] [PDF]
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J. D. Molkentin Calcineurin and Beyond : Cardiac Hypertrophic Signaling Circ. Res., October 27, 2000; 87(9): 731 - 738. [Abstract] [Full Text] [PDF]
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M. Shimoyama, D. Hayashi, Y. Zou, E. Takimoto, M. Mizukami, K. Monzen, S. Kudoh, Y. Hiroi, Y. Yazaki, R. Nagai, et al. Calcineurin Inhibitor Attenuates the Development and Induces the Regression of Cardiac Hypertrophy in Rats With Salt-Sensitive Hypertension Circulation, October 17, 2000; 102(16): 1996 - 2004. [Abstract] [Full Text] [PDF]
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C. Ruwhof and A. van der Laarse Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways Cardiovasc Res, July 1, 2000; 47(1): 23 - 37. [Abstract] [Full Text] [PDF]
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J. A. Hill, M. Karimi, W. Kutschke, R. L. Davisson, K. Zimmerman, Z. Wang, R. E. Kerber, and R. M. Weiss Cardiac Hypertrophy Is Not a Required Compensatory Response to Short-Term Pressure Overload Circulation, June 20, 2000; 101(24): 2863 - 2869. [Abstract] [Full Text] [PDF]
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A. Murat, C. Pellieux, H.-R. Brunner, and T. Pedrazzini Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension J. Biol. Chem., December 22, 2000; 275(52): 40867 - 40873. [Abstract] [Full Text] [PDF]
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M. Asakawa, H. Takano, T. Nagai, H. Uozumi, H. Hasegawa, N. Kubota, T. Saito, Y. Masuda, T. Kadowaki, and I. Komuro Peroxisome Proliferator-Activated Receptor {gamma} Plays a Critical Role in Inhibition of Cardiac Hypertrophy In Vitro and In Vivo Circulation, March 12, 2002; 105(10): 1240 - 1246. [Abstract] [Full Text] [PDF]
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