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10.1146/annurev.physiol.65.092101.142243
Annu. Rev. Physiol. 2003. 65:45–79
doi: 10.1146/annurev.physiol.65.092101.142243
c 2003 by Annual Reviews. All rights reserved
Copyright °
First published online as a Review in Advance on January 9, 2003
CARDIAC HYPERTROPHY:
The Good, the Bad, and the Ugly
Annu. Rev. Physiol. 2003.65:45-79. Downloaded from arjournals.annualreviews.org
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N. Frey1 and E.N. Olson
Department of Molecular Biology, University of Texas Southwestern Medical Center,
Dallas, Texas 75390-9148; email: eric.olson@utsouthwestern.edu; 1Department of
Cardiology (Innere Medizin III), University of Heidelberg, 69115 Heidelberg, Germany
Key Words heart failure, treatment, signaling, cardiomyocyte
■ Abstract Cardiac hypertrophy is the heart’s response to a variety of extrinsic and
intrinsic stimuli that impose increased biomechanical stress. While hypertrophy can
eventually normalize wall tension, it is associated with an unfavorable outcome and
threatens affected patients with sudden death or progression to overt heart failure. Accumulating evidence from studies in human patients and animal models suggests that
in most instances hypertrophy is not a compensatory response to the change in mechanical load, but rather is a maladaptive process. Accordingly, modulation of myocardial
growth without adversely affecting contractile function is increasingly recognized as a
potentially auspicious approach in the prevention and treatment of heart failure. In this
review, we summarize recent insights into hypertrophic signaling and consider several
novel antihypertrophic strategies.
The same thing that makes you live can kill you in the end.
—Neil Young
INTRODUCTION
Cardiomyocyte hypertrophy is the cellular response to an increase in biomechanical stress, be it extrinsic, such as in arterial hypertension or valvular heart disease, or intrinsic, as in familial hypertrophic cardiomyopathy. Cardiac hypertrophy
eventually normalizes the increase in wall tension, thereby abrogating the initial
stimulus. The defining features of hypertrophy are an increase in cardiomyocyte
size, enhanced protein synthesis, and a higher organization of the sarcomere. These
changes in cellular phenotype are preceded and accompanied by the reinduction
of the so-called fetal gene program.
Although hypertrophy in response to pathologic signaling has traditionally been
considered an adaptive response required to sustain cardiac output in the face of
stress, prolonged hypertrophy is associated with a significant increase in the risk
for sudden death or progression to heart failure, independent of the underlying
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cause of hypertrophy (1–3), suggesting that the hypertrophic process is not entirely beneficial. This notion is further supported by observations in clinical trials,
such as the HOPE trial, that inhibition or even regression of cardiac hypertrophy by certain drugs, such as angiotensin-converting enzyme (ACE) inhibitors,
lowers the risk for several endpoints, including death and progression to heart failure, whereas persistence of cardiac hypertrophy (despite similar blood pressure
changes) predicts an adverse outcome (4). These findings raise questions about
whether stress-induced hypertrophy does any good or whether it may be initially
adaptive and only leads to cardiac demise when prolonged. Equally important is
the difference between physiological hypertrophy, as occurs during postnatal development and in response to exercise, and pathological hypertrophy. Strategies
to stimulate the former and inhibit the latter would have obvious therapeutic value
in the setting of heart failure.
If hypertrophy in response to stress were entirely maladaptive, a logical approach would be to identify the underlying molecular events and eventually develop
strategies to prevent or reverse the hypertrophic phenotype to circumvent the subsequent development of heart failure at an early stage. Numerous cardiomyocyteautonomous and endocrine/paracrine pathways have been implicated in the heart’s
molecular response to increased wall stress and the development of hypertrophy.
These pathways have been the focus of multiple excellent reviews in the past
few years (5–7). While we also provide an update on the most recent findings in
the field, our primary focus here is on those pathways that are promising targets
for novel antihypertrophic strategies, as well as on the inherent risks and potential
benefits of new therapeutic options in the treatment and prevention of heart failure.
MOLECULAR PATHWAYS FOR CARDIOMYOCYTE
HYPERTROPHY
Calcineurin-NFAT Signaling
The serine-threonine phosphatase calcineurin is expressed in multiple tissues and
consists of a catalytic A subunit and a regulatory B subunit. Although calcineurin B
is encoded by a single gene, three different calcineurin A subunits (CnAα, CnAβ,
and CnAγ ), with largely overlapping expression patterns, have been described
in vertebrates. The physiological role of calcineurin was initially elucidated in
T-cells in which elevations in cytoplasmic calcium concentrations promote the
association of calmodulin with calcineurin and consequent activation of the enzyme
(8). Calcineurin dephosphorylates transcription factors of the NFAT (nuclear factor
of activated T-cells) family, thereby unmasking nuclear localization signals, which
in turn results in translocation of NFAT proteins to the nucleus and activation of
immune response genes, such as interleukin-2 (reviewed in Reference 9).
More recently, it has been shown that the same principal pathway is also operative in cardiomyocytes. Constitutive activation of calcineurin in transgenic mouse
hearts is sufficient to induce massive cardiac enlargement and eventually heart
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failure (10). A similar, but less dramatic, response was obtained by overexpression of a constitutively nuclear NFAT3 mutant, suggesting that NFAT is also a
principal target of calcineurin-dependent signaling in cardiomyocytes. Although
these studies clearly showed that activation of the calcineurin/NFAT pathway is
sufficient for the development of cardiac hypertrophy, whether calcineurin is also
necessary in this process has been less clear. Confusion surrounding this issue has
arisen largely from conflicting results of in vivo experiments using the calcineurin
inhibitors cyclosporine A (CsA) and FK506 to treat various rodent models of hypertrophy (8, 11, 12). CsA has been shown to prevent hypertrophy of neonatal rat
cardiomyocytes in response to stimulation with angiotensin (AngII) II or phenylephrine (PE) in vitro (8). Consistent with these conclusions, numerous studies have
reported an inhibition or attenuation of hypertrophy by CsA and FK506 in rodents.
However, other well-controlled studies have failed to reveal effects of these drugs
on hypertrophy in vivo. Interpretation of these conflicting results is difficult for
several reasons: (a) Because calcineurin is widely expressed in tissues other than
the heart, inhibition of its activity by CsA or FK506 may modify the cardiac effects via systemic influences, for example, from nephrotoxic effects that create a
secondary prohypertrophic stimulus due to arterial hypertension. (b) The doses of
CsA required to inhibit calcineurin activity in the heart are about 10-fold higher
than those required for immunosuppression and are associated with significant
systemic toxicity, as illustrated by the considerable weight loss of CsA-treated
animals in some studies. (c) The experimental design, specific strain of laboratory animals, method of drug delivery, and/or timing and dosing of calcineurin
inhibitors may complicate interpretation of results. In this regard, in studies employing aortic banding, the position, duration, and severity of the constriction can
affect the signaling pathways that are activated and consequently the sensitivity to
calcineurin inhibition.
These sources of variability can be avoided, at least in part, through genetic
models of calcineurin inhibition. The discovery of several endogenous calcineurin
inhibitors, such as AKAP79, Cabin/Cain, and DSCR/MCIP, has facilitated this
approach. AKAP79 interacts with calcineurin as well as protein kinases A and C
(13), thereby providing a scaffold to integrate these signaling pathways. Overexpression of the calcineurin-binding domain of AKAP79 in cardiomyocytes attenuates PE-induced hypertrophy (14). Similarly, adenovirus-mediated expression of a
truncated form of the noncompetitive calcineurin inhibitor Cain/Cabin (15, 16) in
cardiomyocytes blunted the increase in calcineurin activity and the hypertrophic
response due to serum- and PE/AngII-stimulation. These findings were confirmed
in vivo, where overexpression of the same Cain/Cabin construct resulted in attenuation of both pressure overload and isoproterenol-induced cardiac hypertrophy
(17). Because neither AKAP79 nor Cabin/Cain is expressed at significant levels
in the heart, it is unlikely that either one plays a physiological role in the inhibition
of cardiac calcineurin activity. In contrast, members of another recently identified
family of calcineurin inhibitory proteins termed DSCR/MCIPs (myocyte-enriched
calcineurin-interacting proteins) are enriched in striated muscle and may function
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as endogenous modulators of calcineurin activation in the heart (18–20). This
notion is supported by the finding that expression of MCIP1 itself is highly dependent on calcineurin activity, which is explained by the existence of multiple
NFAT-binding sites in the MCIP1 promoter, which provide the necessary elements for a positive feedback loop (21). MCIP proteins directly bind calcineurin
and inhibit its activity in a competitive and noncompetitive fashion via multiple
interaction domains (22). Intriguingly, overexpression of MCIP1 in transgenic
mouse hearts not only markedly inhibited cardiac hypertrophy and progression to
dilated cardiomyopathy in MCIP/calcineurin double-transgenic mice, but also attenuated isoproterenol- and even exercise-induced increases in cardiac mass (23).
MCIP1 transgenic mice also displayed a significantly impaired hypertrophic response to aortic banding, despite similar aortic pressures proximal to the induced
gradient (24). Remarkably, the lack of compensatory hypertrophy did not result
in deterioration of systolic function, since fractional shortening determined by
echocardiography remained in the normal range up to 3 months after the banding procedure. Similar inhibition of pressure overload hypertrophy by CsA has
been observed in several studies (25, 26). However, in one study, inhibition of left
ventricular hypertrophy (LVH) was associated with an increased susceptibility to
decompensation and heart failure (27). These discrepancies may be explained by
the inherent difficulties with in vivo CsA experiments (as outlined above), but the
principal finding of attenuation of cardiac hypertrophy was consistent. Cardiac
overexpression of a mutated, catalytically inactive calcineurin molecule, which
acts as a dominant-negative protein, also confers protection against hypertrophy
and subsequent development of fibrosis after abdominal aortic constriction (28).
Finally, gene-targeted mice deficient in calcineurin Aβ display a 12% reduction
in basal heart size and are largely resistant to diverse hypertrophic stimuli, such
as pressure overload and infusion of AngII or isoproterenol (29). Interestingly,
the induction of atrial natriuretic factor (ANF) was not impaired in calcineurin
Aβ-null mice, suggesting that the pathways for cardiac hypertrophy and induction
of the fetal gene program can, at least in part, be dissociated.
Taken together, these in vivo studies provide strong evidence for a role of
calcineurin in cardiac hypertrophy resulting from common causes such as pressure
overload. The next generation of genetic mouse models, which is likely to involve
tissue-specific gene ablation, will further refine our knowledge about calcineurindependent signaling in the heart. Moreover, calcineurin signaling is intimately
intertwined with other important hypertrophic pathways, such as those controlled
by glycogen synthase kinase (GSK) 3β and mitogen-activated protein (MAP)
kinase signaling (22, 30), further illustrating its central role in the regulation of
myocardial growth (Figure 1).
That calcineurin appears to be involved in most, if not all, etiologies of pathological cardiac hypertrophy makes it an obvious and attractive therapeutic target
for the prevention and perhaps treatment of heart failure. However, it is less clear
if there is a baseline level of calcineurin activity that may be required to prevent atrophy of the heart. The finding that exercise-induced cardiac hypertrophy
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was attenuated in MCIP1 transgenic hearts suggests that calcineurin also plays
a role in physiological hypertrophy. If this was the case, calcineurin inhibitors
could have potentially harmful effects. In one genetic mouse model of cardiac
hypertrophy, caused by a myosin heavy chain (MHC) mutation implicated in familial hypertrophic cardiomyopathy (FHC), CsA paradoxically exaggerated the
phenotype (31). It is unclear if this response is due to effects of CsA other than
calcineurin inhibition (32) or if calcium-calmodulin-dependent signaling has a different role in FHC compared with more common causes of myocardial hypertrophy
and failure. The latter might be suggested by the finding that diltiazem, a L-type
calcium channel antagonist, could rescue the cardiomyopathic phenotype in this
model (33).
A major challenge for the future will be to tailor calcineurin inhibition spatially
and quantitatively in a way that results in specific inhibition of the detrimental
consequences of increased calcineurin activity in the heart with minimal adverse
effects on its physiological function in the heart, as well as in other tissues. This
approach could be facilitated by a more detailed understanding of the specific
circumstances of calcineurin activation in muscle cells versus other cell types,
which may involve tissue-specific docking molecules, such as calsarcins (34, 35).
PI3K/Akt/GSK-3-Dependent Signaling
Phosphoinositide 3-kinases (PI3Ks) make up a family of enzymes that exhibit
both protein and lipid kinase activity and have been linked to signaling in many
cellular functions, particularly during cell growth, survival, and proliferation (36).
PI3K can be activated by several receptor tyrosine kinases, such as the IGF-1
receptor, as well as G protein-coupled receptors (GPCRs), including α- (37) and
β 2-adrenergic receptors (38, 39). Utilizing gain- and loss-of-function mutations,
PI3K has been shown to control organ size in Drosophila (40). These findings have
recently been extended to the mammalian heart. Naga Prasad et al. showed that
PI3K is activated in pressure overload hypertrophy in a Gβγ -dependent fashion
(41). Moreover, overexpression of a constitutively active PI3K mutant resulted in
cardiac hypertrophy in transgenic mice (42). Conversely, a dominant-negative form
of PI3K led to significantly reduced heart weight/body weight ratios in transgenic
mice. These changes were entirely attributable to differences in cardiomyocyte
size, indicating that PI3K in fact regulates the hypertrophic response rather than
modulating cardiomyocyte proliferation. Interestingly, cardiac function as assessed
by echocardiography was not perturbed in either approach, further suggesting
a direct effect of PI3K activity on cardiomyocyte size, rather than a secondary
adaptation to impaired contractility.
One of the principal targets of PI3K signaling is the serine/threonine kinase
Akt, also known as protein kinase B (PKB). Akt is activated via binding of PI3Kphosphorylated phosphoinositides, which in turn results in its translocation to the
membrane. Full activation requires additional phosphorylation events, including
phosphorylation by phosphoinositide-dependent kinase 1 (PDK1) (43). Similar to
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PI3K, constitutive activation of the Akt homologue Dakt results in increased cell
size in Drosophila (44). Conversely, loss-of-function experiments show a reduction
in cell size without effects on proliferative capacity (45). Again, it can be shown
that transgenic overexpression of Akt/PKB is sufficient to induce significant cardiac hypertrophy in mice without affecting systolic function (46, 47). Constitutive
activation of Akt in skeletal muscle also causes hypertrophy (48).
What are the mediators of PI3K/Akt/PKB-induced hypertrophy? Two welldefined direct downstream targets of Akt are likely candidates: GSK-3 and the
mammalian target of rapamycin (mTor). Rapamycin, an immunosuppressive drug,
binds to its intracellular receptor FKBP12, and this complex subsequently associates with mTor, a large serine/threonine kinase (290 kDa) implicated in the
regulation of protein translation. Binding of rapamycin inhibits the activity of
mTor, thus resulting in impaired protein synthesis and a decrease in cell size via
inhibition of p70S6 kinase and 4EBP1/eIF4E (49). Interestingly, rapamycin is able
to attenuate cardiac hypertrophy secondary to constitutive activation of Akt (46).
Moreover, rapamycin completely blocks the increase in cardiomyocyte size resulting from oxidative stress (50), treatment with PE (51) or AngII (52), as well as fetal
calf serum (53). The induction of fetal genes, such as α-skeletal actin (53) or ANF
(51), was unaffected, suggesting that selective inhibition of protein translation is
sufficient to prevent key features of the hypertrophic response. It will be interesting to see if rapamycin can also prevent cardiac hypertrophy caused by common
events such as pressure overload or in genetic models of hypertrophy, as seen
in the calcineurin transgenic mouse. In addition to mTor, Akt/PKB also directly
phosphorylates GSK-3β, a widely expressed kinase that phosphorylates a series
of serine/threonine residues in the N-terminal regulatory regions of NFAT proteins
(54), thereby masking their nuclear import sequences and promoting translocation
to the cytoplasm and transcriptional inactivation. The activity of GSK-3β is regulated by the phosphorylation status of its serine-9 residue. Phosphorylation of this
site creates an inhibitory pseudosubstrate for the enzyme, rendering it inactive.
Interestingly, several hypertrophic stimuli have been shown to result in phosphorylation of this residue, specifically Akt/PKB directly phosphorylates GSK-3β and
thus inhibits its activity. Although Akt appears to be required for GSK-inactivation
(55), it is not sufficient in vivo because transgenic overexpression of constitutively
active Akt does not increase its phosphorylation status (46, 47), suggesting the
existence of other upstream regulators. The β-adrenergic agonist isoproterenol
(56), as well as ET-1 and PE (57), resulted in GSK-3β phosphorylation in a PI3Kdependent fashion, raising the possibility that inactivation of GSK-3β activity is
required for the hypertrophic response. Haq and colleagues showed that overexpression of a Ser-9 to Ala mutant of GSK-3β, which renders the kinase resistant
to phosphorylation, results in inhibition of ET-1-mediated cardiomyocyte hypertrophy in vitro (57). Overexpression of this GSK-3 mutant in hearts of transgenic
animals also blunts the hypertrophic response to chronic isoproterenol administration and pressure overload, suggesting a broader role of GSK-3β in hypertrophic
signaling than previously anticipated (58). This notion is further supported by a
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recent study by Badorff et al. (59) who demonstrated that treatment of cardiomyocytes with Fas ligand induced hypertrophy and increased GSK-3β phosphorylation. Furthermore, experimental pressure overload in lpr mice, which lack the
Fas-receptor, did not result in cardiac hypertrophy or in GSK-3β inactivation. In
contrast, these mice rapidly developed dilated cardiomyopathy and displayed increased mortality. However, homozygous gld mice (harboring a loss-of-function
Fas ligand mutation), exhibited a normal hypertrophic response to aortic banding,
suggesting that the function of the Fas-receptor in cardiomyocytes extends beyond
mediating Fas ligand–dependent signals.
It remains to be determined if there are GSK-3β targets other than NFAT that
could contribute to its antihypertrophic effects (60). It is notable in this regard that
numerous transcription factors have been shown to be phosphorylated by GSK3β, including c-Jun (61), c-myc (62), STAT (63), and NF-κB (64), all of which
have been implicated, directly or indirectly, in the development of cardiac hypertrophy and thus might mediate GSK-3β signaling. In addition, the transcription
factor GATA4, which regulates several cardiac-specific genes (65), and is sufficient
to induce cardiac hypertrophy (66), is phosphorylated by GSK-3β (67). GATA4
phosphorylation resulted in nuclear export, thereby inhibiting GATA4-dependent
transcription. GSK-3β may also confer antihypertrophic effects via nontranscriptional pathways. GSK-3β phosphorylates eukaryotic initiation factor (EIF) 2B
(68), thus inhibiting translation and potentially cardiomyocyte hypertrophy in a
fashion similar to inhibition of mTor-dependent signaling by rapamycin.
An interesting feature of transgenic mice that overexpress both GSK-3β
(Ser-9 to Ala) and calcineurin is that despite inhibition of cardiac hypertrophy,
ANF and b-type natriuretic peptide (BNP) expression levels are increased compared with those in transgenic mice overexpressing just calcineurin (58). Thus the
development of hypertrophy can, at least in part, be dissociated from activation of
the fetal gene program. These findings differ from in vitro experiments in neonatal cardiomyocytes, in which ET-1-induced expression of ANF can be inhibited
by activated GSK-3β (57). However, a dominant-negative PI3K-mutation, which
would be expected to result in enhanced GSK-3β activity, also upregulated ANF
expression in vivo, while suppressing cardiac growth (42). Interestingly, ANF itself
has antihypertrophic properties (69), as indicated by the development of excessive cardiac hypertrophy in mice lacking its main receptor, the guanylyl cyclase
receptor A (70–72). In addition, overexpression of the receptor led to a reduction
in cardiomyocyte size without affects on blood pressure (73). Thus the antihypertrophic effects of GSK-3β might be mediated in part by upregulation of ANF
expression.
Taken together, these data indicate that GSK-3β integrates signals of several hypertrophic pathways and its inactivation seems to be required for the development
of many forms of cardiac hypertrophy. Moreover, there is significant crosstalk
between PI3K/AKT/GSK-3β and other hypertrophic pathways, particularly the
calcineurin/NFAT pathway (Figure 1), indicating a close interdependence of these
two key cardiac growth signaling cascades.
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Transcriptional Control of Cardiac
Hypertrophy by MEF2/HDAC
Many calcium-dependent signaling molecules, including calcineurin, calcium/
calmodulin-dependent protein kinase (CaMK), and MAP kinases are sufficient
to evoke a hypertrophic phenotype in cardiomyocytes and to induce the reprogramming of cardiac gene expression (reviewed in 75, 76). Given that multiple
pathways can elicit a similar molecular response, it appears likely that hypertrophic
pathways ultimately converge on common endpoints and downstream targets. A
major candidate in this regard is the transcription factor MEF2, which integrates
multiple Ca2+/calmodulin-dependent signaling pathways in muscle cells, as well
as neurons and T-lymphocytes (77). Whereas four independent genes encode distinct MEF2 proteins (MEF2A-D) in vertebrates, only two isoforms, MEF2A and
MEF2D, are expressed at significant levels in the adult myocardium. Interestingly, despite high expression levels, MEF2 proteins display only basal levels of
transcriptional activity in the adult myocardium (78) and only become active upon
stimulation (79), thus fulfilling the criteria for a potential integrator of pathological
growth signals.
MEF2 activity is controlled by direct association with histone deacetylases
(HDACs) (4, 5, 7, 9; reviewed in 77). HDACs deacetylate nucleosomal histones,
thus promoting chromatin condensation and transcriptional repression when recruited to target genes via binding of specific transcription factors such as MEF2.
HDAC activity is opposed by histone acetyltransferases (HATs), which relax chromatin and thereby activate target genes. HDACs can be categorized into three
classes, of which class II HDACs are preferentially expressed at high levels in
striated muscle and neurons. Class II HDACs contain N-terminal extensions that
interact with specific cofactors and transcription factors, including MEF2. Moreover, phosphorylation of specific sites within this part of the HDAC molecule
provides a means of regulating these associations. For example, the tight association of MEF2 with class II HDACs and resulting repression of its transcriptional
activity can be relieved by phosphorylation of two CaMK sites and subsequent
nuclear export of HDACs molecules (80).
Recently, we demonstrated that hypertrophic stimuli such as pressure overload
and calcineurin activation result in activation of a HDAC kinase that phosphorylates the serine residues in class II HDACs that regulate the association with MEF2
(81). While we and others have previously shown that transgenic overexpression
of CaMK is sufficient to induce cardiac hypertrophy and is associated with stimulation of MEF2 activity (79, 82, 83), the lack of inhibition of this novel HDAC
kinase by CaMK inhibitors suggests a different kinase as the bona fide HDAC
kinase. Adenoviral-mediated expression of mutant forms of HDAC5 or HDAC9
that lack the regulatory serine residues renders cardiomyocytes resistant to serumor PE-induced upregulation of ANF- and β-MHC expression and cardiomyocyte
hypertrophy. Mice lacking HDAC9 show normal cardiac size and function at early
age but develop spontaneous cardiac hypertrophy at advanced age. Intriguingly,
these animals also show a severely exaggerated response to thoracic aortic banding
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and calcineurin activation, which is mirrored by superinduction of ANF, BNP, and
β-MHC. Taken together, these data support the notion that many, if not all, hypertrophic stimuli converge in the nucleus and that class II HDACs in concert with
MEF2 and potentially other cardiac transcription factors directly interacting with
MEF2, such as GATA and NFAT, constitute the key integrators of these signals.
The existence of a HDAC kinase opens the intriguing possibility that targeted
inhibition of its enzymatic activity might be a new option in the prevention and
treatment of cardiac hypertrophy and failure.
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Hypertrophy Signaling via G Protein–Coupled Receptors
GPCRs play an important role in the regulation of cardiac function and adaptation to changes in hemodynamic burden (84). The most important myocardial
GPCRs include adrenergic (comprised of several subtypes of α- and β-adrenergic
receptors) and muscarinic receptors. These heptahelical receptors are coupled to
three principal classes of heterotrimeric GTP-binding proteins, Gs, Gq/G11, and
Gi, which transduce the agonist- or antagonist-induced signal toward intracellular
effectors such as enzymes and ion channels. All heterotrimeric G proteins consist of the subunits Gα and Gβγ , which upon receptor activation dissociate and
independently activate intracellular signaling pathways.
Gq/G11 Signaling
AngII, ET1, and alpha-adrenergic receptors are coupled to Gq/11 (which in turn
activates phospholipase C), and have all been shown to be sufficient to mediate
cardiomyocyte hypertrophy upon agonist stimulation (85). Moreover, transgenic
overexpression of these receptors (86, 87) as well as their downstream mediator Gq
(88, 89) results in cardiac hypertrophy and subsequently leads to cardiomyopathy
with depressed contractile function. Conversely, combined genetic ablation of the
Gq and G11 genes results in embryonic lethality due to myocardial hypoplasia,
again suggesting an important role of these mediators in the control of cardiac
growth (90). More recently, utilizing a conditional gene-targeting approach, these
findings have been extended to the adult heart. When G11 null mice (which are
viable and have no obvious cardiac defects) are crossed with mice harboring conditional alleles for Gq and subsequently with mice expressing Cre recombinase in
a cardiac-specific fashion, the resulting phenotype is an almost complete lack of
cardiac hypertrophy or activation of the fetal gene program in response to aortic
banding (91), demonstrating a requirement for Gq/G11 for most if not all features
of pressure overload-induced cardiac hypertrophy. Similarly, overexpression of a
dominant-negative mutant of Gq in transgenic hearts attenuated the hypertrophic response to pressure overload due to aortic banding (92). Interestingly, despite a lack
of normalization of wall stress, cardiac contractility was not only preserved but the
transgenic animals displayed a significantly slower pace of deterioration of systolic
function compared with wild-type controls, again suggesting that cardiac hypertrophy is not necessarily adaptive, at least not for the time period (three months)
examined in this study (93). Likewise, mice that lack dopamine β-hydroxylase,
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the essential enzyme for the synthesis of norepinephrine, also exhibit a blunted
hypertrophic response with preserved contractility, further questioning the concept of adaptive hypertrophy (93). Finally, indirect evidence for an important role
of Gq-dependent signaling in hypertrophy also stems from clinical observations
in patients with cardiomyopathy, in which AngII-receptor blockers and ACE inhibitors conferred beneficial effects, such as inhibition of cardiac remodeling, that
exceeded their antihypertensive properties (94).
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Gs Signaling
The most abundant adrenergic receptor in cardiac tissue is the β1-receptor, coupled
to Gs, which in turn activates adenylate cyclase (AC), eventually resulting in positively chronotropic, inotropic, and lusitropic effects on the heart. The less abundant
β2-receptor can couple to both Gs and Gi, which may provide an additional level
of regulation of β-adrenergic signaling (95). Overexpression of β1-receptors in
hearts of transgenic mice initially increases contractile function and responsiveness
to isoproterenol, but eventually results in progressive deterioration of cardiac performance, cardiomyocyte hypertrophy, and fibrosis (96, 97). Similar findings were
obtained with overexpression of Gs in transgenic animals, but surprisingly were
not dependent on activation of AC (98). In contrast, overexpression of AC type VI
does not appear to exert adverse effects on cardiac function and has been reported
to attenuate cardiomyopathic changes, including cardiac hypertrophy in Gq transgenic mice (99, 100). However, transgenic overexpression of PKA, the principal
target of AC, results in dilated cardiomyopathy associated with cardiomyocyte
hypertrophy and fibrosis, suggesting that PKA mediates the detrimental consequences of chronically elevated β-adrenergic signaling and that AC may have
other yet unknown targets with cardioprotective effects (101). Alternatively, the
subcellular localization of the various components of β-adrenergic signaling may
differ in transgenic models compared with the endogenous molecules, thus not
being subjected to the appropriate regulation. In contrast to β1-adrenergic signaling, overexpression of β2-receptors is only deleterious at excessive levels (>100fold), while moderate levels of β2-receptor expression improve basal contractile
function and rescue the cardiomyopathic phenotype of Gq-transgenic mice (102).
These gene dosage effects may reflect the differences in G protein coupling mentioned above, in that increasing levels of β2-receptors eventually predominantly
couple to Gs.
Heart failure is accompanied by impaired β-receptor function through both a
decreased number of receptors and functional uncoupling (103). The latter is believed to be mediated by β-adrenoceptor kinase (βARK) 1, which phosphorylates
the receptor and thereby rapidly decreases its sensitivity to further agonist stimulation. An inhibitory peptide of βARK, βARKct, which contains the Gβγ -binding
site of βARK, was able to attenuate cardiomyopathy secondary to deficiency of
the sarcomeric protein MLP (104). Moreover, βARKct overexpression significantly blunted the development of cardiac hypertrophy in calsequestrin transgenic
mice (105) while delaying systolic dysfunction. Similar and additive results in this
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animal model were obtained with β-blocker therapy, a well-established therapeutic
modality in human heart failure that has been shown to improve survival in affected
patients (106–108). Interestingly, it was recently demonstrated that β-blocker treatment of patients suffering from congestive heart failure is also accompanied by
a molecular rescue of the cardiomyopathic phenotype, including down-regulation
of hypertrophic genes and up-regulation of previously downregulated genes, such
as SERCA2a and alpha-MHC, which may contribute to the beneficial effects of
this treatment option (109).
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Gi Signaling
Both cardiac muscarinic and β2-adrenergic receptors couple through Gi, thus inhibiting AC and directly opposing Gs-dependent signaling. Of note, Gi is upregulated in human heart failure (110, 111) and basal AC activity is impaired, suggesting
that this mechanism may contribute to the cardiomyopathic phenotype. Moreover,
Gi is upregulated in hypertensive hypertrophy before the development of overt failure (112), indicating that Gi up-regulation may precede decompensation. Finally,
conditional overexpression of a Gi-coupled GPCR resulted in cardiomyopathy
and lethal arrhythmias (113), implying that Gi-dependent signaling is sufficient to
cause heart failure.
Small GTP-Binding Proteins and Sarcomeric Signaling
Small G proteins provide a critical link between cell membrane receptors and various signaling pathways. The small G protein family consists of multiple members,
regulating diverse cellular processes such as cell growth, division and survival, organization of the cytoskeleton, membrane trafficking, and cellular motility. They
share a similar molecular t mass (of about 21 kDa) and the ability to be activated by binding of GTP. The GTPase activity of small G proteins hydrolyzes
GTP to GDP, thus returning the molecules to their inactive state. This process is
regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating
proteins (GAPs). Five families of small G proteins have been described (Rho, Ras,
ARFs, Rab, Ran), each consisting of several members (114). The first small G
protein implicated in cardiac hypertrophy, ras, was sufficient to induce a significant increase in cardiac mass when a constitutively activated mutant was overexpressed in transgenic mouse hearts (115). Similarly, expression of this ras-mutant
in neonatal rat cardiomyocytes resulted in hypertrophic gene expression (116),
whereas dominant-negative ras mutants prevented PE-mediated increases in cell
size and protein synthesis (117, 118). Ras signaling is coupled to multiple downstream effectors, including raf, PI3K, Ral-GDS/rac, and the MAP kinase pathways,
all of which participate in the hypertrophic response. Activated ras was recently
shown to promote nuclear localization of NFAT3, whereas a dominant-negative
ras-mutant (N17ras) was able to abrogate the PE-induced increase in NFAT activity (119). Thus it appears that ras functions in the calcineurin signaling pathway in
cardiomyocytes.
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The Rho family of small G proteins, consisting of Rho, Rac, and Cdc42 subfamilies, regulates the cytoskeletal organization of nonmuscle cells (120), as well as
cardiomyocytes (121). In addition, several hypertrophic signaling cascades can be
influenced by Rho-dependent signaling in muscle cells. RhoA activates a variety of
protein kinases, including RhoKinase (ROCK), which in turn promotes activation
of myosin light chain kinase (MLCK). MLCK, which can also be activated by calcium/calmodulin, is sufficient to induce sarcomeric organization in vitro, one of the
hallmarks of the hypertrophic phenotype (122). This raises the question of whether
Rho signaling contributes to this effect. In addition, dominant-negative RhoA mutants, as well as inhibitors of ROCK, can prevent PE-, ET1-, or Gq-stimulated
cardiomyocyte hypertrophy in vitro (123–125), further supporting this notion. In
contrast, overexpression of RhoA in transgenic mouse hearts was not sufficient to
induce ventricular hypertrophy but did lead to cardiac conduction abnormalities
with bradycardia and, ultimately, a dilated phenotype associated with heart failure
(126). While there is some debate about the specificity of dominant-negative Rho
mutants (114), thus further questioning the significance of experiments demonstrating a necessary role for Rho in the development of cardiomyocyte hypertrophy,
a modulating function of Rho-dependent signaling in hypertrophic gene expression
is less controversial. Interestingly, RhoA signaling stimulates the transcriptional
activity of serum response factor (SRF) via changes in actin dynamics (127).
SRF is a MADS-box transcription factor, regulating many muscle-specific genes
through binding to CArG box elements in their promoter/enhancer sequences, including several hypertrophic genes such as ANF and α-skeletal actin. Overexpression of SRF has been shown to induce massive cardiac hypertrophy in transgenic
mice, implying a role for SRF in mediating hypertrophic signaling in vivo (128).
In this regard, we recently identified a novel muscle-specific sarcomere protein,
STARS, that stimulates SRF-dependent transcription in a Rho-dependent fashion
(129). Because STARS is significantly upregulated in both pressure overload- and
calcineurin-mediated cardiac hypertrophy (A. Arai & E.N. Olson, unpublished
results), it is tempting to speculate that this molecule modulates the hypertrophic
phenotype via Rho/SRF. Moreover, activation of the cardiac transcription factor
GATA4 is also influenced by Rho-dependent signals. Both Y-27632, a selective inhibitor of ROCK, and latrunculin B, an inhibitor of actin polymerization, suppress
the ability of ET1 to increase GATA4 DNA-binding activity (130).
Constitutive activation of Rac in cardiomyocytes in vitro (131) and in vivo
(132) results in hypertrophy, whereas a dominant-negative rac mutant (N17rac1)
prevents PE-induced increases in protein synthesis as well as cardiomyocyte size.
Potential mechanisms for these findings include alterations in focal adhesions and
mislocalization of src and paxillin, all of which are regulated in part by Rac. It
is noteworthy that a dominant-negative focal adhesion kinase (FAK) was able to
attenuate the hypertrophic phenotype of cardiomyocytes, as well as the induction
of ANF expression, after either ET-1 (133) or PE stimulation (134). Most recently,
the Rab family of small G proteins has also been implicated in the development
of cardiac hypertrophy. Wu et al. demonstrated that overexpression of Rab1a in
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transgenic mice is sufficient to induce cardiomyocyte hypertrophy in vivo, ultimately resulting in cardiac dilation and failure (135). Although this phenotype
is associated with upregulated expression and altered subcellular localization of
several PKC isoforms, a role for Rab in common causes of hypertrophy, such as
pressure overload, remains to be established.
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MAPK Pathways
MAPK pathways provide an important link between external stimuli and the nucleus via phosphorylation and regulation of multiple transcription factors. On the
basis of sequence homology, MAPKs can be divided into three major subfamilies: extracellularly responsive kinases (ERKs), c-Jun N-terminal kinases (JNKs),
and p38 MAPKs. The latter two groups are also categorized as stress-responsive
MAPKs because they can not only be activated by anabolic stimuli and agonists
of GPCRs, but also by pathological stress such as ischemia or cytotoxic agents
(136). Interestingly, overexpression of MAPK phosphatase 1 (MKP-1), which inhibits all three major branches of MAPK signaling mentioned above, blocked both
agonist-induced hypertrophy in vitro and pressure overload-associated hypertrophy in vivo (137), thus demonstrating a significant role for these pathways in
hypertrophic signaling. Moreover, FGF2 null mice lack a hypertrophic response
to renal hypertension, which is associated with a general defect in MAPK signaling, as demonstrated by significantly blunted activation of ERK, JNK, and p38
MAPKs (138). These effects were dependent on paracrine FGF2 release from cardiac fibroblasts, suggesting an important role for these cells in mediating cardiac
hypertrophy in a MAPK-dependent fashion.
Significant controversy surrounds the potential role of ERK1/2 in hypertrophic
signaling. Whereas Sugden and coworkers reported that depletion of ERK1/2
with antisense oligonucleotides or pharmacological inhibition of MEK1/2 attenuated the hypertrophic response to agonist stimulation in cultured cardiomyocytes
(139, 140), Post et al. (141) could not confirm an inhibition of ANF-induction
when ERK1/2 signaling was inhibited. Moreover, ERK1/2 activation is not observed in transgenic hearts expressing Gq (88). However, a recent in vivo experiment strongly supports the notion that ERK1/2-dependent signaling is sufficient to
evoke a hypertrophic phenotype. Transgenic overexpression of MEK1, a MAPK
kinase that activates ERK1/2, but not JNKs or p38 MAPKs, results in considerable
cardiac hypertrophy (142). In contrast to most hypertrophy models, this phenotype
was associated with supernormal systolic function, whereas the hypertrophic gene
program was induced in a similar fashion as in other pathological hypertrophy
models. The authors suggest that MEK1-dependent signaling may thus constitute
a pathway for physiological hypertrophy. However, because diastolic function appeared to be impaired (a similar combination of supernormal systolic function
and diastolic dysfunction can be observed in patients with hypertrophic obstructive cardiomyopathy), it remains to be seen if this mouse model is able to rescue
dilated cardiomyopathy phenotypes, such as in MLP-deficient mice. Yet another
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MAPK-module, MEK5/ERK5, mediates signals that result in a distinct type of
hypertrophy, eccentric cardiomyocyte hypertrophy, which is observed in volume
overload-associated myocardial growth in vivo (143). Constitutive activation of
MEK5 leads to serial assembly of sarcomeres in vitro, while MEK5 overexpression in transgenic mouse hearts induces a severe form of dilated cardiomyopathy
and sudden death.
MAPKs of the JNK class are directly phosphorylated by either MKK4 or
MKK7, which in turn are regulated by MEKK1 phosphorylation. In cardiomyocytes, mechanical stretching (144) or agonist stimulation by ET-1 (145), PE (146),
or AngII (147) results in rapid phosphorylation of JNK. Moreover, MKK7 is sufficient to induce all features of cardiomyocyte hypertrophy when overexpressed
in cultured cardiomyocytes (148). Conversely, adenovirus-mediated expression of
a dominant-negative MKK4 mutant attenuates the hypertrophic response to ET-1
in vitro (145), as well as pressure overload-induced hypertrophy (149). Further
evidence for an important role of JNK signaling in cardiac hypertrophy stems
from studies in mice with a targeted disruption of the MEKK1 gene, which results in selective attenuation of JNK activity. MEKK1/JNK has been implicated
in the hypertrophic response of cardiomyocytes secondary to Gq-coupled receptor
stimulation (150). Accordingly, in mice both deficient for MEKK1 and transgenic
for Gq, the hypertrophic phenotype, as well as JNK activation of the latter model,
is entirely abrogated (151). Moreover, this effect was associated with improved
systolic function, suggesting that MEKK1 is necessary for most, if not all, adverse
consequences of chronic Gq activation in the heart. In contrast, MEKK1 deficiency
not only failed to prevent pressure-overload hypertrophy due to aortic banding, but
even resulted in accelerated progression to dilated cardiomyopathy (152), suggesting that MEKK1/JNK inhibition is not a generally applicable strategy to prevent
the adverse consequences of cardiac hypertrophy.
The most important activators of p38 MAPKs are MKK3 and MKK6, both
of which are sufficient to induce cardiomyocyte hypertrophy and ANF-induction
in vitro (153). Similar to the other branches of MAPK signaling, p38 activity is
induced in pressure overload (154) and ET-1/PE stimulation (139, 155). In addition, TAK1, which is upstream of MKK3/6, is upregulated and activated in vivo
after aortic banding (156). A constitutively active TAK1 mutant results in cardiac
hypertrophy and subsequently failure in transgenic mice, further implicating this
branch of MAPK signaling in pathological growth of the myocardium (156). Interestingly, p38 phosphorylates several transcription factors involved in hypertrophic
gene expression, including MEF2 (157) and NFAT3 (158).
PKC and Cardiac Hypertrophy
PKC is a ubiquitously expressed serine/threonine kinase, activated predominantly
by Gq/G11-coupled receptors. Multiple studies implicate the various PKC isoforms
in the pathogenesis of cardiac hypertrophy. Phorbol esters, such as PMA, activate
PKC and mimic the prohypertrophic effects of PE-mediated PKC activation on
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cultured cardiomyocytes (159). Moreover, transgenic overexpression of PKC-β
in transgenic hearts is sufficient to elicit cardiac hypertrophy and sudden death
(160). However, these findings could not be confirmed in other studies (161, 162).
Moreover, PKC-β is not necessary for the hypertrophic response to pressure overload or PE infusion, respectively, because targeted ablation of the PKC-β gene
in mice leaves the animal still susceptible to these stimuli (163). PKC-ε has also
been shown to cause compensated cardiac hypertrophy in vivo (164), but a similar
study reported hypertrophy with rapid progression to heart failure (165). Utilizing dominant-negative adenoviral expression constructs, Braz et al. (166) showed
that only PKC-α is both required and sufficient for cardiomyocyte hypertrophy
in vitro, further complicating the issue of the relative importance of PKC isoforms
in hypertrophic signaling. One possibility to reconcile these differences could be
the differential subcellular localization of endogenous versus overexpressed protein, since PKC activity appears to be exquisitely dependent on the appropriate
spatial targeting and association with scaffolding proteins such as RACK and
AKAPs (167).
Gp130/STAT3 Signaling
Gp130 is a promiscuous receptor for several cytokines, including interleukin 6/11,
leukemia inhibitory factor (LIF), and cardiotrophin-1 (CT-1). Although both are
expressed in multiple tissues, CT-1 induces cardiomyocyte hypertrophy in vitro
(168). Moreover, the prohypertrophic peptide Ang II leads to upregulation of LIF,
CT-1, and interleukin-6 (IL-6) (169). Double-transgenic mice for the IL-6 and IL-6
receptors, a combination that leads to constitutive tyrosine phosphorylation and
subsequent activation of gp130, display marked cardiac hypertrophy (170), suggesting a role for this pathway in the regulation of myocardial growth. Induction
of gp130-dependent signaling leads to activation of both MAPK and JAK/STAT
pathways (171). Specifically, STAT3 is translocated to the nucleus in response to
gp130 activation, which results in the induction of genes involved in hypertrophy and survival pathways (172). Overexpression of STAT3 in transgenic mice is
sufficient to induce cardiomyocyte hypertrophy in vitro (173) and in vivo (174).
Conversely, an adenovirus encoding a dominant-negative STAT3 attenuated the
LIF-induced hypertrophic response, including upregulation of ANF (173). Moreover, transgenic overexpression of a dominant-negative mutant of the gp130 receptor results in attenuation of aortic banding–induced cardiac hypertrophy (175).
Similarly, the suppressor of cytokine signaling 3 (SOCS3), which acts as an endogenous inhibitor of JAK-mediated gp130 signaling, suppresses CT-1-induced
cardiomyocyte hypertrophy (176). SOCS3 was recently shown to coimmunoprecipitate with calcineurin in T-cells, and to prevent calcineurin/NFAT-dependent
transcription (177), suggesting that a similar link between these pathways may
exist in (anti-)hypertrophic signaling within cardiomyocytes.
In unstressed mice, cardiac-restricted ablation of the gp130 receptor is not associated with any obvious phenotype (178). However, when challenged with pressure
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overload due to aortic banding, gp130-deficient mice develop dilated cardiomyopathy, associated with massive cardiomyocyte apoptosis. These data demonstrate
the requirement of this signaling cascade for the heart’s adequate adaptation to
biomechanical stress, specifically by promoting cardiomyocyte survival.
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Lipid Metabolism and Cardiac Hypertrophy
Fuel generation in the adult myocardium depends on the mitochondrial oxidation
of long-chain fatty acids to produce ATP. Cardiac hypertrophy is associated with
a suppression of fatty acid oxidation and metabolic reversion of the heart toward
increased glucose utilization, which is characteristic of the fetal heart (179). This
metabolic shift can be viewed as an adaptive response because it decreases myocardial oxygen-consumption per mole of ATP generated. However, it is unclear
at present which maladaptive sequelae, such as increased lipid accumulation, might
result from chronically impaired oxidation of fatty acids in the heart (180). The
genes involved in fatty acid oxidation are regulated primarily by a family of
transcription factors, referred to as peroxisome proliferator-activated receptors
(PPARs). The three PPAR isoforms—α, β/δ, and γ —belong to the superfamily
of nuclear hormone receptors and can be activated by diverse ligands including
unsaturated fatty acids and isoform-specific drugs such as fibrates (PPARα) and
antidiabetic drugs of the thiazolidinedione class (PPARγ ). PPARs heterodimerize
with another nuclear hormone receptor, the retinoic acid receptor RXR, and recruit
coactivators such as CBP/p300 to activate transcription of target genes. In adipose
tissue, PPARγ stimulates transcription of genes involved in lipid metabolism and
promotes adipocyte differentiation. Additional roles for PPARγ have been proposed in other tissues, such as vascular smooth muscle, where PPARγ -dependent
signaling suppresses proliferation and migration (181).
Targeted ablation of the PPARγ gene in genetically engineered mice results
in embryonic lethality due to placental and (secondary) myocardial defects (182),
although unchallenged heterozygous animals show no overt phenotype. However,
Asakawa et al. (183) recently proposed a role for PPARγ -dependent transcription
as a transducer of antihypertrophic signaling in the heart: Heterozygous PPARγ deficient mice displayed an exaggerated hypertrophic response to aortic banding.
Conversely, the PPARγ agonist pioglitazone was able to significantly blunt myocardial hypertrophy in banded wild-type mice and to a lesser degree in heterozygous PPARγ -deficient mice. These findings are further supported by in vitro data
indicating that AngII-induced hypertrophic gene expression and increased cardiomyocyte size can be attenuated by thiazolidinediones (183, 184). A yet unanswered question is the PPAR isoform specificity of the antihypertrophic effect.
Given that PPARα is the predominant cardiac isoform and that both PPARα and
-γ have a partially overlapping ligand profile, it is possible that PPARα mediates hypertrophic signals in cardiomyocytes as well. Indeed, Kelly and colleagues
(185) have shown that PPARα expression is significantly downregulated during
pressure overload hypertrophy associated with the downregulation of several key
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enzymes of lipid metabolism, such as carnitine palmitoyltransferase 1 (CPT-1),
which controls mitochondrial fatty acid uptake. In addition, Jamshidi et al. (186)
demonstrated that a single nucleotide polymorphism within intron 7 of the PPARα
gene independently predicted the degree of LVH brought about by exercise in
healthy volunteers. In contrast, another layer of complexity for the relationship
between cardiac energy metabolism and hypertrophy was added by the observation that agonist-induced PPARα activation leads to contractile dysfunction in rat
hearts subjected to pressure overload without affecting the trophic response (187),
suggesting that PPARα downregulation is an adaptive response to maintain systolic
performance. This notion is further supported by the finding that overexpression
of PPARα in hearts of transgenic mice leads to cardiomyopathy with contractile
dysfunction (188).
The mechanism of PPAR-dependent modulation of cardiac hypertrophy remains unclear. Two principle possibilities exist: (a) The alterations in cardiac lipid
and energy metabolism are an epiphenomenon that is secondary to the underlying
causes of myocardial growth or (b) abnormalities in lipid signaling precede and
directly or indirectly promote the development of cardiac hypertrophy. The latter is
supported by the observation that many inherited disorders of fatty acid oxidation
are accompanied by left ventricular hypertrophy. In addition, several target genes
and modulators of PPAR signaling have been implicated in hypertrophic signaling as well. In this regard, the transcription factor NF-κB has been demonstrated to
be required for the hypertrophic response of neonatal rat cardiomyocytes in vitro
(189). PPARγ agonists potently inhibit activation of NF-κB, suggesting a possible
mechanism for their antihypertrophic properties. Other effectors previously implicated in cardiac maladaptation and negatively regulated by PPAR include ET-1
(190), TNF-α (191), and iNOS (192). Moreover, 9-cis retinoic acid, a ligand of
RXR, the dimerizing partner of PPARs, has also been shown to inhibit hypertrophy of primary cardiomyocytes (193). It remains to be seen which genes within
cardiomyocytes are targeted by PPARγ signaling and if there is crosstalk or feedback with other established hypertrophy-regulating pathways such as adrenergic
signaling or calcineurin/NFAT. The latter is suggested by the recent finding that
the PPARγ 2 gene is a direct target of NFAT signaling in adipocytes, a pathway
controlling adipocyte formation and differentiation (194). In addition, PPARs are
the target of several protein kinases with a role in hypertrophic signaling, including
PKA and MAPKs.
The key component of cellular cholesterol metabolism, hydroxymethylglutaryl
coenzyme A reductase (HMG-CoA), which catalyzes mevalonate synthesis, the
limiting step in cholesterol synthesis, has recently been implicated in hypertrophic
signaling. Inhibition of this enzyme by the cholesterol-lowering drugs of the statin
class resulted in amelioration of cardiomyocyte hypertrophy in several experimental models in vitro and in vivo. Luo et al. demonstrated that simvastatin significantly
attenuated cardiac hypertrophy in rats with pressure overload due to aortic banding (195). Similarly, the hypertrophic and cardiomyopathic phenotype of a double
transgenic rat model with overexpression of both renin and angiotensinogen was
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improved by cerivastatin treatment (196). Moreover, fluvastatin increased survival
in a murine model of heart failure secondary to myocardial infarction (197). This
was associated with attenuation of LV dilation and a lower end-diastolic pressure, suggesting a favorable effect on postinfarction ventricular remodeling. Patel
et al. observed regression of myocardial hypertrophy and fibrosis in transgenic
rabbits overexpressing a β-MHC mutation after treatment with simvastatin (198).
In addition, both Ang II- (199) and noradrenaline- (200) induced cardiomyocyte
hypertrophy was prevented by lovastatin and simvastatin, respectively.
What might be the mechanism of these unexpected effects of statins? Statins
not only inhibit cholesterol synthesis but also the formation of several isoprenoid
intermediates, including farnesyl- and geranylgeranylpyrophosphate, which in
turn isoprenylate multiple substrates such as the small G proteins ras, Rac1, and
RhoA (see above). Prenylation results in membrane targeting and thus activation of these molecules. Because dominant-negative RhoA inhibits PE-induced
cardiomyocyte hypertrophy (123), it appears plausible that this G protein is involved in statin-induced inhibition of the hypertrophic process. To this end, Takemoto et al. (201) found that simvastatin inhibited cardiac hypertrophy due to
aortic banding while simultaneously preventing Rho-geranylgeranylation. Moreover, AngII-induced membrane association of Rac1 and RhoA and subsequent
upregulation of ANF expression was prevented. Laufs and colleagues demonstrated that statins inhibit ANF and MLC-2 expression in spontaneously hypertensive rats, again accompanied by a decrease in GTP binding activity of Rac1 and
RhoA (202).
At present it is not known if the effects described above contribute to the overwhelmingly positive clinical results in statin-treated patients with cardiovascular
disorders, but it is certainly tempting to speculate that this might be the case.
MISCELLANEOUS PATHWAYS IMPLICATED IN
HYPERTROPHIC SIGNALING
MMP/TNF
Matrix metalloproteinases (MMPs), a family of enzymes involved in extracellular
matrix metabolism, are upregulated in postinfarction cardiac remodeling. Moreover, their increased activation appears to contribute to progressive dilation of the
failing heart (203). Accordingly, several studies have demonstrated that pharmacological inhibition of MMPs is beneficial after experimentally induced myocardial
infarction (204, 205) or volume overload (206). More recently, Asakura et al. reported that inhibition of matrix metalloproteinase 12 (ADAM12) attenuated both
cardiac hypertrophy and subsequent dilation secondary to pressure overload (207).
ADAM12 leads to shedding of the heparin-binding epidermal growth factor (HBEGF) in response to G protein–coupled agonists, such as PE, ET-1, or AngII, thus
resulting in transactivation of the epidermal growth factor receptor (EGFR) and
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cardiomyocyte hypertrophy. Pharmacological inhibitors of both ADAM 12 activity
(KB-R7785) and a neutralizing antibody against HB-EGF abrogated hypertrophic
features such as the increase in protein synthesis after PE or AngII treatment. These
beneficial effects were associated with improved cardiac contractility in vivo, suggesting that this approach might be useful in the treatment of cardiac hypertrophy
and failure.
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CHAMP and Cardiomyocyte Hypertrophy
We recently identified a novel cardiac-specific RNA helicase, cardiac helicase activated by MEF2 protein (CHAMP), in a screen for genes regulated by the MEF2C
transcription factor (208). Adenovirus-mediated overexpression of CHAMP in
neonatal cardiomyocytes abrogates both cardiomyocyte growth and ANF expression owing to PE treatment (209). The mechanisms responsible for these observations appear to involve the upregulation of the cell cycle inhibitor p21CIP1, which
had been shown previously to be sufficient to prevent cardiomyocyte hypertrophy
itself (210). CHAMP expression is significantly downregulated in calcineurintransgenic mice, raising the interesting possibility that this phenomenon contributes to the hypertrophic phenotype.
Na/H Exchanger Inhibition
The activity of the cardiac Na/H-exchanger (NHE) is induced in several animal
models of cardiac hypertrophy, including pressure overload (211) and postinfarction remodeling (212), as well as in studies of cultured cardiomyocytes subjected
to mechanical stress (213). What are the physiological consequences of increased
NHE activity in the heart? The resulting elevation in intracellular sodium concentrations in turn promotes a rise of intracellular calcium levels via the Na/Caexchanger (NCX) (214). Elevated calcium levels in cardiomyocytes can result
in stimulation of several signaling cascades promoting cardiac growth, including
calcineurin-, CaMK-, PKC- and MAPK-dependent pathways (74), thus providing a potential mechanism whereby NHE might promote hypertrophy. Accordingly, inhibition of NHE can rescue several models of cardiac hypertrophy
in vivo: Kusumoto et al. demonstrated that the NHE inhibitor cariporide significantly reduced cardiac hypertrophy after myocardial infarction in rats. Moreover,
this antihypertrophic effect was associated with a favorable hemodynamic profile as well, because cariporide decreased end-diastolic pressures and improved
cardiac contractility, while not affecting infarct size or systemic blood pressure
(215). In addition, NHE inhibition could attenuate the cardiomyopathic phenotype of β1-adrenergic receptor transgenic mice, specifically the development
of cardiac fibrosis and the deterioration of contractile function (216). Finally,
cardiac hypertrophy and fibrosis in spontaneously hypertensive rats (SHR) was
markedly attenuated by cariporide treatment (214). Taken together, these data
suggest that NHE inhibition represents an interesting antihypertrophic treatment
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option because it does not appear to be associated with adverse hemodynamic
consequences.
CARDIAC HYPERTROPHY: COMPENSATORY
RESPONSE VERSUS MALADAPTATION
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Is Cardiac Hypertrophy Good, Bad, or Ugly?
It is generally accepted that cardiac hypertrophy can be adaptive in some situations,
specifically in athletes. However, it is less clear if a hypertrophic response to pathological situations, such as chronic arterial hypertension or a myocardial infarction,
is initially a compensatory response (that only later becomes maladaptive) or if
this type of myocardial growth is detrimental from the outset. If the latter were
true one should expect that distinct molecular pathways result in physiological
hypertrophy due to exercise versus pathological hypertrophy due to chronically
increased wall stress. In fact, it has been demonstrated that these different types
of cardiac hypertrophy differ both on the morphological as well as the molecular
level: Exercise-induced hypertrophy is typically not accompanied by an accumulation of collagen in the myocardium (217) and usually does not exceed a modest
increase in ventricular wall thickness. Moreover, Iemitsu and colleagues found
significantly different expression levels for several hypertrophic genes, such as
BNP or ET-1, in spontaneously hypertensive versus exercised rats (218). In addition, Kinugawa et al. (219) reported that the isoform expression of α-/β-MHCs
is regulated in opposite directions in exercise versus pressure overload-induced
cardiac hypertrophy. However, some hypertrophic pathways, such as calcineurindependent signaling, appear to be activated in both pathological and physiological
exercise-induced hypertrophy, as demonstrated by the finding that the calcineurin
inhibitor MCIP can attenuate both phenotypes (23, 24). Taken together, these data
suggest that good (exercise-associated), bad (pathological), and ugly (decompensated) hypertrophy differ at the molecular level, but this notion does not exclude
the possibility that certain pathways may be involved in all phenotypes of cardiac
hypertrophy.
Inhibition of Cardiac Hypertrophy
As outlined above, several genetic and exogenous inhibitors of cardiac hypertrophy
have been described, most of which have only been identified in the past few years
(Table 1). It has become increasingly clear that the initiation and inhibition of
cardiac hypertrophy involves multiple signaling pathways. It thus seems more
appropriate to view hypertrophic signaling as a web that integrates and modulates
a plethora of input signals. Does this mean one can intervene at any level and
expect a similar effect on resulting cardiac phenotype? A more detailed analysis of
the available data suggests that this is not the case. Although several manipulations
result in a similar degree of inhibition of cardiac hypertrophy, the functional
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TABLE 1 Genetic mouse models with attenuation of cardiac hypertrophy
Genetic model
Hypertrophy model
Contractile function
Reference
MCIP1-Tg
Aortic banding
Unchanged
Hill et al. (24)
MCIP1-Tg
CNA-Tg
Improved
Rothermel et al. (23)
MCIP1-Tg
Isoproterenol
Not reported
Rothermel et al. (23)
MCIP1-Tg
Exercise
Not reported
Rothermel et al. (23)
Cain/Cabin-Tg
Aortic banding
Not reported
De Windt et al. (17)
Cain/Cabin-Tg
Isoproterenol
Not reported
De Windt et al. (17)
AKAP79-Tg
Aortic banding
Not reported
De Windt et al. (17)
AKAP79-Tg
Isoproterenol
Not reported
De Windt et al. (17)
CNA(dn)-Tg
Aortic banding
Not reported
Zou et al. (28)
CNAβ (−/−)
Aortic banding
Not reported
Bueno et al. (29)
CNAβ (−/−)
Angiotensin II
Not reported
Bueno et al. (29)
CNAβ (−/−)
Isoproterenol
Not reported
Bueno et al. (29)
GSK-3β-Tg
CNA-Tg
Not reported
Antos et al. (58)
GSK-3β-Tg
Isoproterenol
Not reported
Antos et al. (58)
lpr (−/−)
Aortic banding
Worsened
Badorff et al. (59)
Gq(dn)-Tg
Aortic banding
Improved
Esposito et al. (93)
Dbh (−/−)
Aortic banding
Unchanged
Esposito et al. (93)
Gq/G11 (−/−)
Aortic banding
Unchanged/worsened
Wettschureck et al. (91)
βARKct
Calsequestrin-Tg
Improved
Harding et al. (105)
β2-AR-Tg (low)
Gq-Tg
Improved
Dorn et al. (102)
MKP1-Tg
Aortic banding
Not reported
Bueno et al. (137)
MKP1-Tg
Isoproterenol
Not reported
Bueno et al. (137)
RGS4-Tg
Aortic banding
Worsened
Rogers et al. (220)
MEKK1 (−/−)
Gq-Tg
Improved
Minamino et al. (151)
FGF2 (−/−)
Aortic banding
Unchanged
Schultz et al. (138)
Ad-MKK4(dn)
Aortic banding
Unchanged
Choukroun et al. (144)
gp130(dn)-Tg
Aortic banding
Unchanged
Uozumi et al. (175)
S100β
Norepinephrine
Unchanged
Tsoporis et al. (225)
consequences can differ greatly (Table 1). For example, transgenic mice overexpressing MCIP or GSK3-β, respectively, markedly attenuate the hypertrophic response to pressure overload while maintaining a normal systolic function (24, 58).
In contrast, overexpression of RGS4, a GTPase-activating protein for heterotrimeric G proteins, which inhibits cardiac hypertrophy to a similar degree as the
interventions mentioned above, results in rapid cardiac decompensation, depressed
systolic function, and increased mortality (220).
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These examples illustrate that the hypertrophic response can be dissociated
from contractile (dys-)function. This notion is further supported by the fact that
several genetic models of increased contractility, such as ablation of the phospholamban gene (221) or overexpression of S100A1 (222), are not associated
with a change in cardiac mass. Conversely, S100A1-null mice have a significantly
impaired contractile function after pressure overload compared with wild-type
controls, although they display no difference in the hypertrophic response (223).
Similarly, cardiac hypertrophy can be dissociated from the induction of the hypertrophic gene program: While GSK-3β was able to significantly attenuate cardiac
hypertrophy in calcineurin-transgenic mice, it did not reduce ANF expression but
rather superinduced the fetal gene program. Likewise, chronic treatment with L-Nnitro-L-arginine methyl ester (L-NAME), an inhibitor of nitrous oxide synthesis,
causes severe hypertension in rats with levels of systolic wall stress comparable
to that induced by aortic banding (224). Although banded rats developed severe
cardiac hypertrophy, this response was completely absent in L-NAME-treated animals. Moreover, the lack of hypertrophy did not result in heart failure, whereas the
hypertrophic gene program was upregulated in both experimental groups. However, important differences were also found compared with the classical response:
β-MHC expression was not induced at significant levels, and SERCA-2 expression
was significantly upregulated, both of which may contribute to the hemodynamic
compensation.
This detailed dissection of hypertrophic signaling may eventually make it possible to specifically exploit therapeutically desired aspects of hypertrophy (i.e.,
induction of certain genes or increased sarcomere organization) while inhibiting
others (i.e., the increase in cardiac mass, which is associated with adverse events
such as arrhythmias). A potentially interesting target for a therapeutic intervention
is the transcriptional response in cardiac hypertrophy because it appears to be regulated by relatively few molecules, such as the transcription factors MEF2, NFAT,
and GATA4. Moreover, histone deacetylases (HDACs) negatively regulate these
mediators of pathological myocardial growth, and thus represent a particularly
attractive target for an inhibitory approach.
Although several reports now support the concept that inhibition of cardiac
hypertrophy might be beneficial, even if the original stimulus (i.e., increased wall
stress) persists, one has to keep in mind that these experimental approaches typically had only a short observation span. Therefore, it is conceivable that long-term
inhibition of cardiac hypertrophy in a heart with increased wall stress might eventually still result in failure. Whatever the successful antihypertrophic intervention
ultimately is going to be, its effect has thus to be sustained and even more importantly, it should not negatively affect contractile function. In addition, antihypertrophic agents will likely have to be combined with complementary strategies, such as the modulation of calcium cycling, to enhance contractile function and
the inhibition of the neurohormonal response to achieve the goal of successfully
treating and preventing heart failure in patients.
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Figure 1 Signaling pathways involved in cardiomyocyte hypertrophy.
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Annual Review of Physiology,
Volume 65, 2003
CONTENTS
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Frontispiece—Jean D. Wilson
xiv
PERSPECTIVES, Joseph F. Hoffman, Editor
A Double Life: Academic Physician and Androgen Physiologist,
Jean D. Wilson
1
CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor
Lipid Receptors in Cardiovascular Development, Nick Osborne
and Didier Y.R. Stainier
Cardiac Hypertrophy: The Good, the Bad, and the Ugly, N. Frey
and E.N. Olson
Stress-Activated Cytokines and the Heart: From Adaptation to
Maladaptation, Douglas L. Mann
23
45
81
CELL PHYSIOLOGY, Paul De Weer, Section Editor
Cell Biology of Acid Secretion by the Parietal Cell, Xuebiao Yao
and John G. Forte
Permeation and Selectivity in Calcium Channels, William A. Sather
and Edwin W. McCleskey
Processive and Nonprocessive Models of Kinesin Movement,
Sharyn A. Endow and Douglas S. Barker
103
133
161
COMPARATIVE PHYSIOLOGY, George N. Somero, Section Editor
Origin and Consequences of Mitochondrial Variation in Vertebrate
Muscle, Christopher D. Moyes and David A. Hood
Functional Genomics and the Comparative Physiology of Hypoxia,
Frank L. Powell
Application of Microarray Technology in Environmental
and Comparative Physiology, Andrew Y. Gracey and
Andrew R. Cossins
177
203
231
ENDOCRINOLOGY, Bert W. O’Malley, Section Editor
Nuclear Receptors and the Control of Metabolism,
Gordon A. Francis, Elisabeth Fayard, Frédéric Picard, and
Johan Auwerx
261
vii
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CONTENTS
Insulin Receptor Knockout Mice, Tadahiro Kitamura, C. Ronald Kahn,
and Domenico Accili
The Physiology of Cellular Liporegulation, Roger H. Unger
313
333
GASTROINTESTINAL PHYSIOLOGY, John Williams, Section Editor
Annu. Rev. Physiol. 2003.65:45-79. Downloaded from arjournals.annualreviews.org
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The Gastric Biology of Helicobacter pylori, George Sachs,
David L. Weeks, Klaus Melchers, and David R. Scott
Physiology of Gastric Enterochromaffin-Like Cells, Christian Prinz,
Robert Zanner, and Manfred Gratzl
Insights into the Regulation of Gastric Acid Secretion Through Analysis of
Genetically Engineered Mice, Linda C. Samuelson and Karen L. Hinkle
349
371
383
NEUROPHYSIOLOGY, Richard Aldrich, Section Editor
In Vivo NMR Studies of the Glutamate Neurotransmitter Flux
and Neuroenergetics: Implications for Brain Function,
Douglas L. Rothman, Kevin L. Behar, Fahmeed Hyder,
and Robert G. Shulman
401
Transducing Touch in Caenorhabditis elegans, Miriam B. Goodman
and Erich M. Schwarz
429
Hyperpolarization-Activated Cation Currents: From Molecules
to Physiological Function, Richard B. Robinson and
Steven A. Siegelbaum
453
RENAL AND ELECTROLYTE PHYSIOLOGY, Steven C. Hebert, Section Editor
Macula Densa Cell Signaling, P. Darwin Bell, Jean Yves Lapointe,
and János Peti-Peterdi
Paracrine Factors in Tubuloglomerular Feedback: Adenosine, ATP,
and Nitric Oxide, Jürgen Schnermann and David Z. Levine
Regulation of Na/Pi Transporter in the Proximal Tubule,
Heini Murer, Nati Hernando, Ian Forster, and Jürg Biber
Mammalian Urea Transporters, Jeff M. Sands
Terminal Differentiation of Intercalated Cells: The Role of Hensin,
Qais Al-Awqati
481
501
531
543
567
RESPIRATORY PHYSIOLOGY, Carole R. Mendelson, Section Editor
Current Status of Gene Therapy for Inherited Lung Diseases,
Ryan R. Driskell and John F. Engelhardt
The Role of Exogenous Surfactant in the Treatment of Acute Lung
Injury, James F. Lewis and Ruud Veldhuizen
Second Messenger Pathways in Pulmonary Host Defense,
Martha M. Monick and Gary W. Hunninghake
585
613
643
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CONTENTS
Alveolar Type I Cells: Molecular Phenotype and Development,
Mary C. Williams
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SPECIAL TOPIC: LIPID RECEPTOR PROCESSES, Donald W. Hilgemann,
Special Topic Editor
Getting Ready for the Decade of the Lipids, Donald W. Hilgemann
Aminophospholipid Asymmetry: A Matter of Life and Death,
Krishnakumar Balasubramanian and Alan J. Schroit
Regulation of TRP Channels Via Lipid Second Messengers,
Roger C. Hardie
Phosphoinositide Regulation of the Actin Cytoskeleton,
Helen L. Yin and Paul A. Janmey
Dynamics of Phosphoinositides in Membrane Retrieval and
Insertion, Michael P. Czech
SPECIAL TOPIC: MEMBRANE PROTEIN STRUCTURE, H. Ronald Kaback,
Special Topic Editor
Structure and Mechanism of Na,K-ATPase: Functional Sites
and Their Interactions, Peter L. Jorgensen, Kjell O. Håkansson,
and Steven J. Karlish
G Protein-Coupled Receptor Rhodopsin: A Prospectus,
Slawomir Filipek, Ronald E. Stenkamp, David C. Teller, and
Krzysztof Palczewski
ix
669
697
701
735
761
791
817
851
INDEXES
Subject Index
Cumulative Index of Contributing Authors, Volumes 61–65
Cumulative Index of Chapter Titles, Volumes 61–65
ERRATA
An online log of corrections to Annual Review of Physiology chapters
may be found at http://physiol.annualreviews.org/errata.shtml
881
921
925