Circulation Research. 2000;87:731-738
(Circulation Research. 2000;87:731.)
© 2000 American Heart Association, Inc.
Calcineurin and Beyond
Cardiac Hypertrophic Signaling
Jeffery D. Molkentin
From the Department of Pediatrics, University of Cincinnati, Division of
Molecular Cardiovascular Biology, Children’s Hospital Medical Center,
Cincinnati, Ohio.
Correspondence to Jeffery D. Molkentin, PhD, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail molkj0{at}chmcc.org\\ © 2000 American Heart Association, Inc.
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Abstract
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Abstract—In
response to increased ventricular wall tension
or neurohumoral stimuli,
the myocardium undergoes an adaptive
hypertrophy response that
temporarily augments pump function.
Although initially beneficial,
sustained cardiac hypertrophy
can lead to decompensation and
cardiomyopathy. Recent studies
have focused on characterizing the
molecular mechanisms that
underlie cardiac hypertrophy. An increasing
number of signal
transduction pathways have been identified as
important regulators
of the hypertrophic response, including the
low–molecular
weight GTPases (Ras, RhoA, and Rac), mitogen-activated
protein
kinases, protein kinase C, and calcineurin. This review will
discuss
an emerging body of evidence that implicates the
calcium-calmodulin–activated
protein phosphatase calcineurin as a
physiological regulator
of the cardiac hypertrophic response. Although
the sufficiency
of calcineurin to promote cardiomyocyte hypertrophy in
vivo
and in vitro is established, its overall necessity as a
hypertrophic
mediator is currently an area of ongoing debate. The use
of
the calcineurin-inhibitory agents cyclosporine A and FK506 have
suggested
a necessary role for calcineurin in many, but not all, animal
models
of hypertrophy or cardiomyopathy. The evidence implicating a
role
for calcineurin signaling in the heart will be weighed against
a
growing body of literature suggesting necessary roles for
a diverse
array of intracellular signaling pathways, highlighting
the
multifactorial nature of the hypertrophic
program.
Key Words: calcineurin • cardiac hypertrophy • transcription • heart failure • signaling
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Introduction
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Cardiac
hypertrophy is defined as an increase in heart size
resulting from an
increase in cardiomyocyte cell volume. The
hypertrophic growth of the
myocardium is initiated by a wide
array of endocrine, paracrine, and
autocrine growth factors
in response to increased workload, injury, or
intrinsic defects
in contractile performance. Although it is initially
an adaptive
response that temporarily augments or maintains cardiac
output,
sustained cardiac hypertrophy is a leading cause of the
development
of heart failure and sudden death in
humans.
1 2
To begin to
understand the molecular determinants of the hypertrophic
response,
recent investigation has focused on identifying and
characterizing
intracellular signal transduction pathways in the
heart.
Traditionally, discussion of intracellular signaling has
been largely associated with the actions of protein kinases such as the
mitogen-activated protein kinases (MAPKs) or the actions of G proteins.
However, intracellular protein phosphatases are also important signal
transduction factors that regulate growth and stress responses in a
wide variety of cell types. One such phosphatase is the
calcium-calmodulin–activated protein phosphatase 2B (PP2B), or
calcineurin. Calcineurin is a serine-/threonine–specific
phosphatase that is uniquely activated by sustained elevation in
[Ca2+]i.3 4 5
The active calcineurin holoenzyme is composed of a 59- to 63-kDa
catalytic subunit referred to as calcineurin A, a 19-kDa calcium
binding protein referred to as calcineurin B, and the calcium binding
protein
calmodulin.3 4
Three mammalian calcineurin A genes have been identified (
, ß, and
) that share 81% sequence identity across a 350-amino acid stretch
that constitutes the catalytic domain
(Figure 1
). Even more striking, the calcineurin A and Aß
genes share 
99% amino acid sequence identity between mouse and
human species, suggesting tight evolutionary selection. The calcineurin
A and Aß gene products are expressed in a relatively ubiquitous
and overlapping pattern throughout the body, whereas calcineurin A
is expressed in a more restricted pattern that includes the
testis.6 7 8 9
Both calcineurin A and Aß proteins, but not A, are present in
cardiomyocytes.10
Calcineurin enzymatic activity is uniquely regulated by
displacement of the C-terminal autoinhibitory domain within the
catalytic subunit in response to calmodulin binding to an adjacent
domain
(Figure 1
). Calcineurin catalytic activity is inhibited by
the immunosuppressive drugs cyclosporine A (CsA) and FK506 through
complexes with cyclophilins and FKBP12,
respectively.3 4
The identification of calcineurin as a target for CsA and FK506
suggested a critical role for this phosphatase in the regulation of
T-cell reactivity and cytokine gene expression. The mechanism whereby
calcineurin promotes T-cell activation and cytokine induction has been
largely attributed to the family of transcriptional regulators referred
to as nuclear factor of activated T cells (NFAT). Calcineurin directly
binds to NFAT transcription factors in the cytoplasm, resulting in
their dephosphorylation and subsequent translocation into the nucleus
(Figure 2). Five NFAT transcription factors have been
identified, of which NFATc1 through NFATc4 are regulated by
calcineurin-mediated dephosphorylation, whereas NFATc5 is
constitutively nuclear and not subject to calcineurin
regulation.11 12
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Figure 2. Figure 2. The mechanism of
calcineurin-NFAT signaling was first established in T cells. Activation
of the T-cell receptor (TCR) promotes increased
[Ca2+]i, which
saturates calmodulin, resulting in calcineurin activation and
subsequent dephosphorylation of NFAT transcription factors.
Dephosphorylated NFAT translocates to the nucleus, where it interacts
with the promoters of cytokine genes. Immunosuppressive drugs CsA and
FK506 complex with immunophilin proteins, which subsequently bind and
inhibit calcineurin. T-cell activation also utilizes MAPK (JNK)
activation to promote transcriptional activation through activator
protein-1 (AP-1), which synergizes with NFAT factors to promote
inducible gene
expression.
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Calcium and Calcineurin
Signaling in the Heart
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Although calcium is the fundamental regulator of
actin-myosin
crossbridge interaction and contraction, it has also been
implicated
as an inducer of cardiac hypertrophy in response to
neurohumoral
stimulation, stretch, and
pacing.
13 14 15 16
Many studies have
identified alterations in calcium handling in the
failed myocardium
such that the amplitude of the intracellular calcium
transient
is decreased and
prolonged.
17 Such
studies have suggested the
hypothesis that alterations in intracellular
calcium handling
progressively exacerbate a hypertrophic or
cardiomyopathic phenotype,
in part, through sustained activation of
calcium-sensitive signal
transduction pathways. The recent
identification of calcineurin
as a potential hypertrophic regulatory
factor supports such
a hypothesis.
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Sufficiency of Calcineurin and NFAT to Induce
Cardiac Hypertrophy
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Calcineurin was originally proposed as a hypertrophic
signaling
factor based on the identification of NFATc4 as a GATA4
interacting
factor in the
heart.
18 To
characterize the potential involvement
of calcineurin in cardiac
hypertrophy, an activated truncation
mutant of calcineurin was
overexpressed in the hearts of transgenic
mice.
18 Eleven
separate transgenic lines were generated that each demonstrated
a
profound hypertrophic response (2- to 3-fold increase in heart
size)
that rapidly progressed to dilated heart failure within
2 to 3 months
(Figure 3
). Such data implicated calcineurin as
a sufficient
inducer of the hypertrophic response and as a potential
causative
factor associated with the transition to decompensation
and heart
failure. In vitro, infection of cultured neonatal
cardiomyocytes with a
calcineurin-expressing adenovirus also
induced a hypertrophic response,
supporting the sufficiency
of calcineurin as a hypertrophic
mediator.
19
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Figure 3. Figure 3. Histological analysis
demonstrates the profound cardiac hypertrophy response that
characterizes the calcineurin transgenic mouse. Top, Hematoxylin and
eosin–stained histological sections from a calcineurin transgenic and
a wild-type heart at 2 months of age. Bottom, Wheat germ agglutinin
(WGA)-TRITC–stained histological sections show the significant
increase in myofibrillar cross-sectional area from a calcineurin
transgenic
heart.
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That NFAT transcription factors act downstream of
calcineurin in the heart was suggested by the observation that
transgenic mice expressing a constitutively nuclear NFATc4 protein
(N-terminal truncation) also developed profound hypertrophy within 2 to
3 months of age.18
However, overexpression of full-length (cytoplasmic) NFATc4 did not
produce detectable hypertrophy, suggesting a critical role for
calcineurin-mediated activation of NFAT proteins in the
heart.18 Although
these studies have demonstrated a sufficiency for calcineurin and NFAT
transcription factors as mediators of the cardiac hypertrophic
response, a number of questions remain. The requirement of calcineurin
and NFAT as endogenous regulators of physiological stress responses in
the heart remains largely unproven and an active area of investigation.
In addition, the degree to which NFAT factors are required to mediate
the hypertrophic effects of calcineurin in the heart remains unresolved
(see Role of NFAT Transcription Factors in the Heart,
below).
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Calcineurin Activation in Cardiac
Hypertrophy
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Treatment of cultured neonatal cardiomyocytes with the
calcineurin-inhibitory
agent CsA was reported to attenuate
agonist-induced hypertrophy
in
vitro.
18 This
initial observation suggested that calcineurin
is likely activated in
cultured cardiomyocytes in response to
agonist stimulation.
Accordingly, agonist stimulation (phenylephrine,
angiotensin II, and
1% FBS) significantly increased calcineurin
enzymatic activity in
cultured cardiomyocytes, which was associated
with an increase in both
calcineurin Aß mRNA and protein
levels.
10 The
observed increase in calcineurin Aß protein in association
with
myocyte hypertrophy suggests a secondary mechanism (apart
from calcium)
whereby calcineurin activity can be regulated
in the heart.
Endothelin-1–stimulated hypertrophy of cultured
cardiomyocytes also
induced a significant (3-fold) increase
in calcineurin activity,
although protein levels were not
examined.
20 In
addition, electrical pacing-induced hypertrophy of cultured
cardiomyocytes
was inhibited by CsA, further implicating calcineurin as
a regulator
of cardiomyocyte hypertrophy in
vitro.
21
Collectively, these
studies demonstrated that calcineurin enzymatic
activity was
upregulated in cultured cardiomyocytes in association with
the
hypertrophic response.
Activation of calcineurin in response to pathophysiological
stress in vivo remains more controversial. Calcineurin enzymatic
activity was upregulated by 2-fold in hearts from juvenile
tropomodulin transgenic mice, a model of dilated heart
failure.22 This
increase was later shown to be associated with a 3-fold increase in
total calcineurin A protein content in the
heart.23 Similarly,
pressure-overload hypertrophy in aortic-banded rats and
exercise-induced cardiac hypertrophy in the rat were each associated
with increased calcineurin enzymatic activity in the
heart.24 25 26 27
In contrast, one group reported no change in cardiac calcineurin
activity in response to pressure-overload
stimulation,28
whereas another group reported decreases in calcineurin
activity.29
The disparate reports discussed above suggest that either
differences exist between experimental animal models with respect to
calcineurin activation or, more likely, quantification of calcineurin
phosphatase activity from tissue or cell lysates is problematic.
Experimentally, calcineurin enzymatic activity is determined by
monitoring the release of free phosphate (radioactively or chemically)
from a phosphorylated substrate such as the RII peptide from whole-cell
or tissue protein extracts. Because multiple phosphatases are present
in cell extracts, parallel reactions are required in which calcineurin
activity is specifically inhibited with the autoinhibitory peptide
domain. The resultant activity is then calculated as the difference
between the blocked and unblocked
states.24 A mixture
of phosphatase inhibitors is required to reduce background phosphatase
activity and enhance sensitivity, a necessary strategy that also has
the effect of partially inhibiting calcineurin activity (okadaic acid).
An additional consideration relates to the lability of calcineurin due
to oxidation of the Fe-Zn active center, which underscores the
observation that calcineurin is 10 to 20 times more active in situ
compared with purified protein
extracts.30
Despite technical concerns surrounding the calcineurin
activity assay, a more important consideration is the relevant
information that such an assay gives and its inherent limitations. Even
if the in vitro assay is properly performed, it is only an indirect
measure of activity and, as such, is inadequate for assessing
calcineurin activity in vivo. The calcineurin phosphatase assay
measures peak activity in the presence of saturating levels of
calmodulin and hence probably only reflects the content of calcineurin
available for activation. Given these concerns, it can be argued that a
simple Western blot for calcineurin A protein might suffice. Indeed, we
have observed that increased enzymatic activity in the heart is often
associated with a secondary increase in calcineurin A protein
levels.22 23 24
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Use of CsA and FK506 as Calcineurin-Inhibitory
Agents in the Heart
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Although CsA has been reported to attenuate
agonist-induced
cardiomyocyte hypertrophy in
vitro,
18 19 20 21
its effectiveness
in vivo is problematic. CsA and FK506 each prevented
the phenotypic
manifestations of hypertrophic and dilated
cardiomyopathy in
3 separate transgenic mouse models of intrinsic heart
disease.
22 In the
same report, CsA administration to aortic-banded rats
over 6 days
prevented the induction of cardiac hypertrophy
(Table
).
22
Although these results suggested new theoretical strategies
for
treating certain forms of human heart disease, enthusiasm
was tempered
by the known side effects of CsA and FK506 in humans
(see Clinical
Implications section, below). Furthermore, 4 subsequent
studies
concluded that calcineurin inhibitors did not significantly
block
pressure-overload hypertrophy in either aortic-banded
mice or rats,
suggesting that CsA and FK506 might not be effective
antihypertrophic
agents
(Table
).
29 30 31 32
However, 6 reports
demonstrated a partial or complete inhibition of
load-induced
cardiac hypertrophy with CsA or FK506 in aortic-banded
rats
or mice
(Table
).
28 29 31 32
In addition, CsA prevented exercise-induced
cardiac hypertrophy in the
rat,
26 attenuated
hypertrophy and
histopathology in renin and angiotensin transgenic
rats,
35 attenuated
myocardial infarction–induced cardiac hypertrophy
in the
rat,
36 and reduced
cardiac hypertrophy in activated
G
q transgenic
mice.
37 In contrast,
CsA did not prevent cardiac
hypertrophy due to hypertension in the
spontaneously hypertensive
rat.
28 Whereas most
pharmacologic studies support a role for calcineurin
in the
hypertrophic response, the negative accounts may reflect
factors such
as drug dosage, differences in the surgical preparations,
sex, age, or
animal strain. For example, the drug dosages that
have been used to
date vary between 5 and 40 mg/kg of CsA injected
either once or twice a
day for periods of time between 6 days
and 5 weeks.
Although technical details might certainly underlie
some of the conflicting data discussed above, an alternative
consideration is the degree to which specific animal models
require/utilize a calcineurin-dependent signaling pathway or other
hypertrophic signaling pathways. For example, 2 transgenic mouse models
of hypertrophic cardiomyopathy have been reported that are resistant to
CsA treatment. Transgenic mice overexpressing a mutated retinoid X
receptor- or constitutively nuclear NFATc4 in the heart develop
cardiac hypertrophy that is insensitive to calcineurin
inhibition.22 23
In addition, CsA did not block hypertrophy in ascending aortic-banded
juvenile mice, a model of gradual onset pressure overload during
postnatal
development.29 Taken
together, these observations underscore the multifactorial nature of
the cardiac hypertrophic response and suggest calcineurin-independent
pathways for regulating myocyte reactivity.
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Targeted Inhibition of Calcineurin Attenuates
Cardiomyocyte Hypertrophy
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Another aspect of controversy surrounding CsA and FK506
studies
in animal models of hypertrophy pertains to drug specificity.
CsA
and FK506 each affect multiple intracellular targets besides
calcineurin,
suggesting alternative mechanisms whereby such drugs might
attenuate
the hypertrophic
response.
38 39 40
To address the issue of
specificity, an alternate approach using the
noncompetitive
calcineurin-inhibitory domains from the
calcineurin-interacting
proteins Cain/Cabin-1 and A-kinase anchoring
protein 79 (AKAP79)
were
used.
41 42 43
Adenovirus expressing the calcineurin-inhibitory
domains of Cain or
AKAP inhibited calcineurin activity and attenuated
phenylephrine- and
angiotensin II–induced hypertrophy
in cultured
cardiomyocytes.
10
The inhibition of hypertrophy
by Cain and AKAP adenoviral infection was
similar to the inhibition
observed with CsA and FK506, suggesting
calcineurin as the determinative
factor.
10
Calcineurin activity is also negatively regulated by the inhibitory
proteins
MCIP1 and MCIP2 (DSCR1 and ZAKI-4), which are each highly
expressed
in the heart and skeletal
muscle.
44 45
It will be interesting
to generate and characterize transgenic mice
expressing these
various calcineurin-inhibitory proteins in the heart
to more
specifically evaluate the importance of calcineurin as a
regulator
of cardiac hypertrophy in vivo. Alternatively, targeted
disruption
of the calcineurin A
and/or Aß genes might also provide
important
genetic evidence confirming or disputing calcineurin as a
necessary
regulator of cardiac hypertrophy in vivo
.Indeed, both calcineurin
A
and Aß knockout mice are
viable, which should permit
a final, definitive analysis of the role of
calcineurin in the
hypertrophic response in the near future. However,
because the
viability of double-null calcineurin A
and Aß mice is
uncertain,
transgenic dominant-negative–based approaches might still
be
of significant value.
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Conserved Role of Calcineurin and NFAT in
Skeletal Muscle Hypertrophy
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A number of recent reports have implicated calcineurin
and NFAT
in the differentiation and hypertrophy of skeletal muscle,
suggesting
a conservation in the regulatory program that controls
striated
muscle cell growth. Specifically, calcineurin promoted
skeletal
muscle myoblast hypertrophy downstream of an IGF-1–dependent
signaling
pathway.
46 47
CsA treatment also blocked the growth response of cultured
human
myoblasts, attenuated muscle regeneration in response
to acute injury
in vivo,
48 and
prevented skeletal muscle hypertrophy
in response to muscle
overloading.
49
Adenovirus-mediated gene
transfer of activated calcineurin in cultured
C2C12 and Sol8
myoblasts potentiated their growth, whereas inhibition
of calcineurin
with Cain or AKAP inhibitory domains attenuated myocyte
growth.
50 NFATc1,
NFATc2, and NFATc3 have all been implicated as downstream
effectors of
calcineurin in the regulation of myoblast differentiation
or subsequent
hypertrophy in cultured skeletal muscle
cells.
47 48 50
Collectively, these studies suggest a conservation in
the regulatory
program that controls striated muscle cell hypertrophy
through a
calcineurin- and NFAT-dependent pathway.
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Role of NFAT Transcription Factors in the
Heart
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Whereas NFAT transcription factors are important
downstream
effectors of calcineurin in T cells, neurons, and skeletal
muscle
myoblasts, we must also consider the alternative hypothesis
that
calcineurin regulates the cardiac hypertrophic response
independently
of NFAT factors. Indeed, calcineurin also regulates
activity of the
transcriptional regulatory factors nuclear factor-
B,
Elk-1, and
myocyte enhancer factor-2
(MEF-2).
40 51 52 53 54 55
That MEF-2 might be an important hypertrophic transcription
factor was
recently suggested by the observation that transgenic
mice expressing a
dominant-negative MEF-2 factor in the heart
presented with diminished
developmental hypertrophic
growth.
56 As a final
consideration, it has been difficult to directly
demonstrate endogenous
NFAT nuclear translocation in response
to hypertrophic agonists in
cardiac myocytes. Such a description
in the literature may be lacking
for technical reasons related
to low NFAT protein concentration and/or
the lack of reliable
antibodies. To ultimately resolve the contribution
of NFAT transcription
factors as downstream mediators of calcineurin in
the heart,
it will be necessary to evaluate the ability of NFAT
knockout
mice to mount a hypertrophic response.
However, analysis of mRNA distribution in mammals has
demonstrated that all 5 NFAT genes are expressed in the heart,
suggesting that gene-targeting approaches in the mouse will be
complicated by redundancy
issues.12 57 58 59
Despite this concern, single or combinatorial knockout strategies might
still implicate NFAT factors as calcineurin effectors in the heart.
Accordingly, NFATc4- and NFATc3-null mice are viable and should permit
such an evaluation in the near future. Alternatively, NFAT-specific
dominant-negative approaches in transgenic mice might also provide
significant insights, similar to strategies used in T
cells.60
Calcineurin may also regulate the cardiac hypertrophic
response in coordination with other intracellular signal transduction
pathways. Indeed, calcineurin promotes c-Jun N-terminal kinase (JNK),
extracellular signal–regulated kinase (ERK), and protein kinase C
(PKC) and 
activation in cardiac
myocytes.61 This
observation is consistent with reports in T cells in which calcineurin
interconnects (cross talks) with PKC and MAPK signaling pathways in the
regulation of cytokine gene
expression.62 63
However, the mechanisms whereby a phosphatase (calcineurin) might
promote the activation of kinases such as JNK and PKC in either T cells
or cardiac myocytes is uncertain. A working hypothesis is that
calcineurin initiates a primary transcriptional response through NFAT,
Elk-1, nuclear factor-B, or MEF-2 factors to set in motion autocrine
regulatory mechanisms (angiotensin II or endothelin-1 release) that
promote re-entrant signaling through G protein–coupled receptors and
receptor tyrosine kinases leading to the secondary activation of PKC
and MAPK factors. However, we cannot rule out the possibility that
calcineurin might regulate one or more cytoplasmic regulatory factors
to indirectly promote PKC and MAPK activation. For example,
calcineurin, PKC, and PKA all share a common cytoplasmic docking
protein, AKAP79, which suggests a mechanism whereby multiple signaling
pathways are coordinately regulated by localization to common
cofactors.64
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Beyond Calcineurin: Integrated Signaling
Networks
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In T cells, calcineurin functions in concert with MAPK
and PKC
signaling pathways to regulate cytokine gene expression and
ultimately
the immune response itself. Accordingly, gene knockout
approaches
in the mouse have demonstrated that calcineurin A
,
PKC
, and
JNK are each required for productive T-cell reactivity in
vivo,
suggesting that multiple intracellular signaling pathways are
necessary
for orchestrating the immune
response.
65 66 67
This paradigm
likely extends to cardiac myocytes given the emerging
literature
that demonstrates a necessary role for diverse intracellular
regulatory
factors in the hypertrophic response. For example,
transgenic
mice expressing a dominant-negative G
protein in the
heart failed
to undergo hypertrophy in response to pressure
overload.
68
Similarly,
expression of RGS4, a GTPase-activating protein, in the
hearts
of transgenic mice attenuated pressure-overload hypertrophy,
supporting
a critical role for G proteins as transducers of
hypertrophic
stimuli.
69
Adenovirus-mediated gene transfer of a dominant-negative SEK1
factor
(MAPK-kinase-4) blocked the hypertrophic response of
aortic-banded
rats, suggesting a critical role for MAPK factors in
vivo.
70
Cardiac-restricted deletion of the gp130 receptor in mice profoundly
affected
the pressure-overload response, implicating an important role
for
gp130 in cardiac
homeostasis.
71
Lastly, fibroblast growth factor
2 knockout mice and
AT
2 knockout mice each demonstrated a dramatic
reduction
in cardiac hypertrophy induced by acute aortic
banding.
72 73
In vitro, several studies have demonstrated necessary roles
for
signaling factors such as Ras, Raf-1, rac-1, p38, MAP/ERK
kinase 1,
focal adhesion kinase, and calcineurin in mediating
aspects of
cardiomyocyte
hypertrophy.
10 74 75 76 77 78 79 80 81
The above-mentioned studies underscore the multifactorial
nature of the cardiac hypertrophic response and suggest a great deal of
molecular heterogeneity in the process referred to as cardiac
hypertrophy. These studies suggest a model of reactive signaling in the
heart whereby certain central pathways are absolutely necessary for the
initiation and maintenance of a balanced hypertrophy response, similar
to the complexity of signaling involved in T-cell reactivity and
cytokine production. In addition, many central regulatory pathways
likely interconnect or cross talk with one another in the orchestration
of the hypertrophic response. For example, pharmacological inhibition
of calcineurin is associated with inhibition of PKC, PKC, and JNK
p54 in the heart.61
Such cross talk might occur through direct molecular interconnections
or indirectly through autocrine release of peptide growth factors
leading to re-entrant signaling at the cell
membrane.
|
Clinical Implications
|
|---|
Although calcineurin-inhibitory drugs can attenuate
cardiac
hypertrophy in some rodent models of pressure overload, their
usefulness
in humans is doubtful. Both CsA and FK506 have a number of
side
effects in humans, including nephrogenic and neurogenic toxicity
as
well as
immunosuppression.
82
Indeed, chronic CsA therapy in
human transplant patients induces renal
toxicity leading to
hypertension and secondary cardiac
hypertrophy.
83 This
observation
suggests that CsA is actually associated with cardiac
hypertrophy
in humans (albeit secondary) when given at
immunosuppressive
doses. To inhibit cardiac hypertrophy in animals, a
10-fold
higher dose of CsA is used than is commonly administered in
human
immunosuppressive
regimens.
84 Such
dosing could be related
to higher calcineurin protein content in
cardiomyocytes relative
to T and B cells or to differences in tissue
accessibility.
In any event, because a large number of humans develop
renal
failure and hypertension on the lower dosage, CsA is effectively
eliminated
as a treatment for cardiac hypertrophy in humans. It is
possible,
however, that future cardiac-specific methods of inhibiting
calcineurin
activity will be developed and of potential
benefit.
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Acknowledgments
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This work was supported by NIH Grants
HL69562, HL-62927, and HL52318 and by the Pew Charitable Trust
Foundation. I would like to thank Drs Katherine Yutzey and Jeffrey
Robbins for critical evaluation of this
manuscript.
Received August 14, 2000;
revision received September 12, 2000;
accepted September 15, 2000.
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Abstract
Introduction