Journal of Molecular and Cellular Cardiology 97 (2016) 245–262

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Journal of Molecular and Cellular Cardiology

journal homepage: www.elsevier.com/locate/yjmcc

Review article

Physiological and pathological cardiac hypertrophy

Ippei Shimizu a,b,⁎, Tohru Minamino a,⁎⁎
a
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
b
Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan

a r t i c l e i n f o a b s t r a c t

Article history: The heart must continuously pump blood to supply the body with oxygen and nutrients. To maintain the high
Received 29 November 2015 energy consumption required by this role, the heart is equipped with multiple complex biological systems that
Received in revised form 10 May 2016 allow adaptation to changes of systemic demand. The processes of growth (hypertrophy), angiogenesis, and met-
Accepted 1 June 2016
abolic plasticity are critically involved in maintenance of cardiac homeostasis. Cardiac hypertrophy is classified as
Available online 2 June 2016
physiological when it is associated with normal cardiac function or as pathological when associated with cardiac
Keywords:
dysfunction. Physiological hypertrophy of the heart occurs in response to normal growth of children or during
Cardiac hypertrophy pregnancy, as well as in athletes. In contrast, pathological hypertrophy is induced by factors such as prolonged
Heart failure and abnormal hemodynamic stress, due to hypertension, myocardial infarction etc. Pathological hypertrophy is
Angiogenesis associated with fibrosis, capillary rarefaction, increased production of pro-inflammatory cytokines, and cellular
Akt dysfunction (impairment of signaling, suppression of autophagy, and abnormal cardiomyocyte/non-cardiomyo-
Autophagy cyte interactions), as well as undesirable epigenetic changes, with these complex responses leading to maladap-
Inflammation tive cardiac remodeling and heart failure. This review describes the key molecules and cellular responses
Epigenetic modification
involved in physiological/pathological cardiac hypertrophy.
MicroRNA
© 2016 Elsevier Ltd. All rights reserved.
Metabolism

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
2. Classification of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
3. Various types of cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
4. Mechanism of physiological cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
4.1. Mechanosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.2. Thyroid hormone/thyroid hormone receptor signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.3. Insulin-like growth factor-1/insulin-like growth factor-1 receptor/Akt signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.4. Insulin/insulin receptor (IR)/Akt signaling—as a pathway mediating physiological hypertrophy . . . . . . . . . . . . . . . . . . . . . 248
4.5. Akt is a key molecule for cardiac hypertrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
4.6. Role of sirtuins in modulating Akt signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
5. Mechanisms of pathological cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
5.1. Calcineurin-nuclear factor of activated T cells (NFAT) signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
5.2. β-adrenergic receptor signaling and Ca2 +/calmodulin-dependent kinase II signaling . . . . . . . . . . . . . . . . . . . . . . . . . . 250
5.3. cGMP/protein kinase G signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
5.4. Protein kinase C and mitogen-activated protein kinase signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
5.5. Insulin/insulin receptor (IR)/Akt signaling—as a pathway mediating pathological hypertrophy . . . . . . . . . . . . . . . . . . . . . . 251
6. Modifiers of cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
6.1. Endogenous factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
6.1.1. Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
6.1.2. Modification of DNA and histones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

⁎ Correspondence to: I. Shimizu, Department of Cardiovascular Biology and Medicine, Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and
Dental Sciences, 1-757 Asahimachidori, Chuo-ku, Niigata 951-8510, Japan.
⁎⁎ Correspondence to: T. Minamino, Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachidori,
Chuo-ku, Niigata 951-8510, Japan.
E-mail addresses: ippeishimizu@yahoo.co.jp (I. Shimizu), t_minamino@yahoo.co.jp (T. Minamino).

http://dx.doi.org/10.1016/j.yjmcc.2016.06.001
0022-2828/© 2016 Elsevier Ltd. All rights reserved.
246 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262

6.1.3. MicroRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

6.1.4. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
6.2. Exogenous factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
6.2.1. Fibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
6.2.2. Endothelial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
6.2.3. Immune cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
6.3. Endogenous and exogenous factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
6.3.1. Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
7. Angiogenic response in physiological versus pathological cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

1. Introduction It is estimated that 50% of heart failure patients have preserved LV

Mammalian cardiomyocytes generally exit the cell cycle soon after
birth, so most cardiomyocytes are terminally differentiated in adults
and do not proliferate under physiological conditions. However, cardiac
tissue exhibits plasticity that enables the heart to respond to environ-
mental demands, and cells can grow, shrink, or die in reaction to various
physiological or pathological stresses. Cardiac hypertrophy is classified
as physiological when associated with normal cardiac function or as
pathological when associated with cardiac dysfunction.
Normal physiological enlargement of the heart chiefly occurs
through hypertrophy of cardiomyocytes in response to growth of the
body or exercise, and the enlarged cardiomyocytes receive adequate
nourishment due to corresponding expansion of the capillary network.
Structural or functional cardiac abnormalities do not occur in this set-
ting, and physiological hypertrophy is generally not considered to be a
risk factor for heart failure. In contrast, pathological hypertrophy is asso-
ciated with production of high levels of neurohumoral mediators, he-
modynamic overload, injury and loss of cardiomyocytes. In the
pathological setting, cardiomyocyte growth exceeds the capacity of
the capillaries to adequately supply nutrients and oxygen, leading to
cardiac hypoxia and remodeling in rodents [1,2]. Because cardiac hyper-
trophy plays a central role in cardiac remodeling and is an independent
risk factor for cardiac events, understanding this process is critically
important.
Cardiac dysfunction is associated with a complex spectrum of path-
ophysiological changes, including capillary rarefaction, metabolic de-
rangement, sarcomere disorganization, altered calcium handling,
inflammation, cellular senescence, cell death and fibrosis. Due to such
complexity, no simple therapeutic approach is adequate for the
management of this condition. There is some overlap between the
mechanisms of physiological and pathological cardiac hypertrophy,
since there is evidence for a central role of Akt signaling or
mechanotransduction in physiological hypertrophy, while neurohor-
monal factors or continuously overloaded biomechanical stress
induce multiple signaling pathways, including Akt, in pathological
hypertrophy.
2. Classification of heart failure
There are two broad types of heart failure, heart failure with reduced
(HFrEF) and heart failure with preserved (HFpEF) ejection fraction.
HFrEF develops through the accumulation of myocardial damage and
progressive loss of cardiomyocytes, and is commonly caused by myo-
cardial infarction, hypertensive heart disease, or cardiomyopathy. Oxi-
dative stress present within the cardiomyocytes induces
cardiomyocytes death and replacement fibrosis [3]. Cardiomyocyte
loss promotes alterations within the extracellular matrix and contrib-
utes to left ventricular (LV) dilatation and eccentric LV remodeling [4].
ejection fraction and described as HFpEF. In addition to preserved LV
ejection fraction, concentric remodeling and diastolic LV dysfunction
are characteristically observed in HFpEF patients. Overweight/obesity,
hypertension, diabetes mellitus, chronic obstructive pulmonary disease,
anemia and chronic kidney disease induces a systemic inflammatory
state and these systemic disorders are thought to increase the risk of de-
veloping HFpEF. Structural alterations of HFpEF are characterized with
cardiomyocyte hypertrophy and interstitial fibrosis, and functional
change is consisted of incomplete relaxation of myocardial strips and in-
creased cardiomyocyte stiffness [5–8]. Replacement fibrosis is usually
thought not to develop in HFpEF because cell death does not predomi-
nantly develop in HFpEF. Whether HFrEF and HFpEF are distinct patho-
logical conditions or rather represent a syndrome that exists across a
spectrum is yet to be defined [9]. Heart failure, defined on clinical
terms, derives from numerous different disorders, however, under-
standing mechanisms of cardiac hypertrophy continues to be essential
for describing pathologies in this critical condition.
3. Various types of cardiac hypertrophy
Heart responses to environmental conditions and able to grow or
shrink. Heart increases in size and depending on the types, strength
and duration of stimuli, it results in physiological or pathological cardiac
hypertrophy. Physiological hypertrophy is characterized with normal or
enhanced contractile function coupled with normal architecture and or-
ganization of cardiac structure [10]. Pathological hypertrophy associates
with increased cardiomyocytes death and fibrotic remodeling, and it is
characterized with reduced systolic and diastolic function that often
progresses towards heart failure. Primary triggering events of cardiac
hypertrophy are mechanical stress and neurohumoral stimulation, and
these contribute for the modulation of various cellular responses includ-
ing gene expression, protein synthesis, sarcomere assembly, cell metab-
olism, leading to the development and progression of cardiac
hypertrophy [11–13]. Accumulating evidence indicates that pathologi-
cal and physiological hypertrophy differs in the signaling pathways
that drives these processes. Studies suggest that left ventricular hyper-
trophy provides short-term benefit and long-term harm, however,
mechanism regulating this transition from adaptive to maladaptive hy-
pertrophy is yet to be defined [14].
Cardiac hypertrophy can also be classified into various variants de-
pending on the geometries of the heart, whether it develops eccentric
or concentric growth (Fig. 1). Eccentric hypertrophy develops with vol-
ume overload and non-pathological eccentric hypertrophy shows in-
creased ventricular volume with a coordinated growth in wall and
septal thickness. In this condition, cardiomyocytes grow both in length
and width. Pathological eccentric hypertrophy generally develops
with cardiac diseases such as myocardial infarction and dilated cardio-
myopathy, and lead to ventricular dilatation with preferential lengthen-
ing of cardiomyocytes. Concentric hypertrophy shows an increase in
 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262 247

Fig. 1. Geometry of the heart and signaling pathways contributing mainly for physiological cardiac hypertrophy. Cardiac hypertrophy can be classified as eccentric or concentric
hypertrophy based on the geometry of the heart. Mechanotransduction and Insulin/IGF-1/Akt signaling induce physiological hypertrophy, but excessive activation of these pathways
promotes pathological hypertrophy. Thyroid hormone induces physiological hypertrophy and also has the potential to ameliorate pathological hypertrophy. SIRT3 and SIRT6
suppresses Akt, thereby inhibit hypertrophic responses.

free wall and septal thickness associated with reduced left ventricular
dimension. Cardiomyocytes typically increase in thickness more than
in length [6,15], and this condition usually develops under pathological
conditions such as hypertension or valvular diseases, although in some
settings, exercise such as wrestling is known to induce non-pathological
concentric hypertrophy [16]. Cardiac hypertrophy is generally thought
to initially develop as an adaptive response to reduce wall stress thereby
diminish oxygen demand according to the law of Laplace. This is a
pioneering stress adaptation hypothesis demonstrating that ventricular
wall stress is proportional to both ventricular pressure and cavity radius
and inversely proportional to ventricular thickness [17]. Mechanisms
regulating the geometry of the heart is elegantly reviewed by Molkentin
et al. [18] Several complex mechanisms are reported to be involved in
the molecular basis of physiological and pathological cardiac
hypertrophy.
4. Mechanism of physiological cardiac hypertrophy
Enlargement of the heart in response to growth, exercise, and preg-
nancy is associated with maintenance of normal cardiac function and is
described as “physiological” hypertrophy. There is a linear relationship
between the increase of body weight and cardiac weight. The increase of
cardiac weight during growth is largely attributable to enlargement
of cardiomyocytes, and there is an almost 3-fold increase of cardiomyo-
cyte diameter in humans during development from infants to adults.
Physiological hypertrophy differs from the pathological hypertrophy
that occurs in patients with hypertension, valvular heart disease or
myocardial infarction. Negative cardiac remodeling including fibrosis
does not predominantly develop in physiological hypertrophy, and
this response is thought harmless and even beneficial in healthy indi-
viduals. It is generally accepted that both cardiac size and function are
dependent on angiogenesis, and dysregulation of coordination between
cardiomyocyte growth and angiogenesis in the heart has a causal role in
the shift from adaptive cardiac hypertrophy to heart failure [1,2,19].
Physiological cardiac hypertrophy develops through finite signals
from growth hormones and mechanical forces. Within a physiological
range, growth hormones such as insulin, insulin-like growth factor1
and thyroid hormone, and mechanical forces induce physiological cardi-
ac hypertrophy via the activation of several signalings such as PI3K
(phosphoinositide 3-kinase), Akt, AMP-activated protein kinase and
mTOR (mammalian target of rapamycin) pathways [11,20–24].
248 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
4.1. Mechanosensors
Cardiomyocytes is equipped with a machinery to sense and respond
to mechanical load, and this system is described as
mechanotransduction. Mechanotransduction enables cardiomyocytes
to convert mechanical stimuli into biochemical events through the
modulation of signaling molecules. Several protein complexes are re-
ported to link to mechanotransduction and mechanotransmission at
three key sites within the cardiac myocyte/cytoskeleton; the sarcomere,
the intercalated disc and the sarcolemma. Proteins acting as
mechanotransducers responding upon mechanical load are the initial
step in the process that drives physiological and pathological cardiac hy-
pertrophy. Mechanotransduction and its downstream molecules func-
tion initially as adaptive responses, however, prolonged and abnormal
loading conditions promotes maladaptive cardiac remodeling, associat-
ed with altered physiological function and pathological cardiac hyper-
trophy (Fig. 1). At the sarcomere, titin and muscle LIM protein (MLP)
are the two molecules broadly studied to be involved in force transmis-
sion and sensing that would regulate cardiac hypertrophy [25,26]. Both
proteins form a vast network with interacting proteins such as titin-Cap
(TCAP), calsarcin-1, four-and-a half-LIM domain protein-1 (FHL1) and
muscle-specific ankyrin repeat protein (MARP) family members. In ad-
dition to these molecules existing at the sarcomere, several other mole-
cules are located in the intercalated disc (such as N-cadherin) and
sarcolemma (such as Integrins, Vinculin, Talin, Caveolin-3 and Dystro-
glycan), and reported to modulate physiology in the heart including car-
diac hypertrophy. The molecular mechanisms of mechanotransduction
in cardiac hypertrophy and failure, and their therapeutic potentials are
elegantly reviewed by Sheikh et al. [27] As described in this review,
mechanisms underlying mechanotransduction are yet to be defined
and further description is beyond the scope of this review.
4.2. Thyroid hormone/thyroid hormone receptor signaling
Thyroid hormone exerts its biological effect by binding to thyroid
hormone receptors (TRα and TRβ), and thyroid hormone-TR signaling
pathway is involved in regulating cardiac contractility, structure, and
electrophysiology. Whether thyroid hormone promotes physiological
cardiac hypertrophy in adults is still controversial, however, its role in
postnatal hypertrophy is well accepted. After birth, thyroid hormone in-
creases dramatically in children [23]. Thyroid hormone promotes the
physiological growth of the neonatal cardiomyocytes, and this is medi-
ated by the activation of p38MAPK and PI3K/Akt/mTOR signaling [24,
28]. Thyroid hormone optimizes cardiac geometry, which is known to
contribute for improving myocardial performance [29]. Continuous in-
jection of thyroid hormone promoted cardiac hypertrophy in rats and
this was not associated with fibrosis and even reduced collagen gene ex-
pression [30,31]. In a rat LV pressure overload model, thyroid hormone
promoted non-significant increase in LV dry weight, and suppressed
heart failure. Myocytes treated with thyroid hormone were
hypertrophied, but this was associated with an increase in α-MHC and
sarcoplasmic reticulum Ca2+ (SERCA) expression, similar to physiolog-
ical hypertrophy [32]. In a rat pathological hypertrophy model with
myocardial infarction, thyroid hormone changed cardiac geometry
and improved systolic cardiac function [33]. Studies indicate that thy-
roid hormone can convert pathological to physiological cardiac hyper-
trophy and details are reviewed and discussed by Pantos et al [34].
4.3. Insulin-like growth factor-1/insulin-like growth factor-1 receptor/Akt
signaling
Insulin-like growth factor 1(IGF-1) is structurally similar to insulin
and is mainly synthesized and secreted by the liver in response to stim-
ulation by growth hormone, although it is also produced by extrahepat-
ic tissues and acts locally in a paracrine or autocrine fashion. IGF-1 has a
molecular weight of 7.6 kDa and shares 50% homology with insulin. It
shows high affinity for the IGF-1 receptor (IGF-1R) and relatively low af-
finity for the insulin receptor (IR). The circulating level of IGF-1 is in-
versely correlated with cardiovascular disease [35]. Thus, a low IGF-1
level is associated with a high risk of coronary artery disease [36,37]. A
low IGF-1 level also predicts a worse prognosis in patients with myocar-
dial infarction [38], and elderly persons with low IGF-1 levels have an el-
evated risk of heart failure [39]. IGF-1 is generally thought to have a
cardioprotective role. For example, IGF-1 was reported to protect
cardiomyocytes against oxidative stress and ameliorate cardiac dys-
function after myocardial infarction [40,41]. In the heart, IGF-1 is pre-
dominantly produced and secreted by fibroblasts, and fibroblast
derived IGF-1 promoted cardiomyocyte hypertrophy and contributed
to suppress cardiac dysfunction [42]. IGF-1 is involved in regulating
cell proliferation, differentiation, metabolism, and survival, and its ex-
pression is critically important for normal prenatal/postnatal growth
and development, with its biological effects being predominantly medi-
ated via the IGF-1R. This receptor is reported to have dual activities,
with the IGF-1/IGF-1R/Akt/mammalian target of rapamycin (mTOR)
and IGF-1/IGF-1R/ERK signaling pathways being described as canonical
pathways, while IGF-1/Gi/phospholipase C (PLC)/inositol 1,4,5 triphos-
phate (IP3)/Ca+ signaling is considered to be a non-canonical pathway
and crosstalk occurs between these pathways [43]. The effects of in-
creased IGF-1/IGF-1R signaling have been studied in skeletal muscle
and in the myocardium. IGF-1 induces skeletal muscle hypertrophy,
generally via Akt/mTOR signaling [44], or via the Akt-independent
mTOR/p70S6K pathway in some settings [45]. In athletes, IGF-1 level
in cardiac tissue (but not endothelin (ET)-1 or angiotensin II (AngII))
was higher than in control subjects, and serum IGF-1 level was shown
to increase with exercise [46,47]. These results suggested the contribu-
tion of IGF-1 in promoting physiological cardiac hypertrophy upon ex-
ercise. Genetic deletion of IGF-1 leads to significant reduction of body
weight during development and usually results in embryonic lethality
or death from respiratory failure shortly after birth. IGF-1R null mice
show dramatic phenotypic changes, with their birth weight being only
45% of that for healthy littermates and 100% mortality from respiratory
failure [48,49]. Forced expression of IGF-1 in the heart promotes cardiac
hypertrophy with cardiac dysfunction [50] or without cardiac dysfunc-
tion [51] depending on the transgenes used, the effect of IGF-1 on
non-cardiomyocytes, or the observation period. A murine model of car-
diomyocyte-specific overexpression of Igf1r mimics physiological, not
pathological, cardiac hypertrophy by promoting gene transcription
that is not predominantly related to pathological cardiac growth [22].
Interestingly, Igf1r deletion does not lead to any differences in the base-
line phenotype of adult cardiomyocytes. However, cardiac growth in re-
sponse to exercise was inhibited in one study, but not in another study,
possibly due to different exercise protocols [21,52]. Consistent with the
findings by Ikeda et al., suppression of IGF-1 signaling did not affect the
hypertrophic response to chronic β-adrenergic stimulation [53]. The re-
sults obtained by modulation of IGF-1 signaling vary between studies
and animal models, possibly because of its role in a broad spectrum of
biological activities that include cardiac growth, aging, metabolism,
cell proliferation, and cell survival. However, it seems that activation
of IGF-1 signaling is beneficial within a certain finite physiological
range, contributing to the maintenance of cardiac homeostasis (Fig.1).
4.4. Insulin/insulin receptor (IR)/Akt signaling—as a pathway mediating
physiological hypertrophy
Insulin is a hormone secreted by pancreatic β-cells that was discov-
ered in 1921 and was initially identified as a critical regulator of the
blood glucose level. Over time, evidence has been obtained to demon-
strate that insulin has a broad range of biological activities, and it is
now known that insulin signaling coordinates glucose/lipid metabo-
lism, protein synthesis, cell growth and differentiation, apoptosis, and
senescence [54,55]. Insulin binds to the insulin receptor (IR), after
which insulin receptor tyrosine kinase phosphorylates insulin receptor
 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
substrate (IRS) and activates PI3K, leading to generation of
phosphoinositide-3,4,5 triphosphate that mediates the phosphorylation
and activation of Akt. It is generally accepted that insulin signaling is
critically important for the normal physiological growth and develop-
ment of cardiac tissue (Fig.1). Cardiac specific overexpression of Akt
was shown to enhance cardiac function with left ventricular hypertro-
phy [56]. The Akt-mTOR signaling was increased in a murine treadmill
exercise model [57]. PI3K-Akt signaling is reported to increase Ca2 +
handling and improve cardiac inotropism, and was mediated partially
via the stabilization of L-type Ca2 + channel (LTCC) [58]. Preferential
translocation of Akt to the sarcoplasmic reticulum was shown to en-
hance cardiomyocyte contractility without promoting cardiac hypertro-
phy by the phosphorylation of phospholamban [59]. Homozygous
deletion of Ir in cardiac tissue leads to a significant decrease of cardio-
myocyte size and heart weight, with persistence of a fetal gene expres-
sion pattern and reduced cardiac function [20]. Depletion of Ir in the
heart induces mitochondrial dysfunction by reducing the expression
of fatty acid oxidation genes and their regulators [60,61]. Systemic de-
pletion of Irs1 or Irs2 led to the postnatal general growth retardation
[62,63]. Recently, an interesting paper by Ikeda et al has described the
role of IGF-1 and IR mediated signaling in regulating hypertrophic re-
sponse induced by exercise. Homozygous deletion of Igf1r (Igf1r−/−)
or Ir (Ir−/−) in cardiac tissue is associated with normal or reduced base-
line cardiac growth, respectively, while the hypertrophic response to
exercise is normal in both cases. Igf1r−/− mice lacking one Ir allele in
cardiomyocytes (Igf1r−/− Ir+/−) and Ir−/− mice lacking one Igf1r allele
in cardiomyocytes (Igf1r+/− Ir−/−) show attenuation of cardiac hyper-
trophy in response to exercise. The phenotype of Igf1r+/− Ir−/− mice
is more severe, suggesting that the IR and its downstream molecules
are more closely involved in physiological hypertrophy related to exer-
cise [52]. It remains unclear whether crosstalk occurs between the IR
and IGF-1R during development of pathological cardiac hypertrophy.
Both insulin/IR signaling and IGF-1/IGF-1R signaling share downstream
effectors such as Akt, so further studies are needed to determine wheth-
er one signaling pathway is more beneficial than the other.
4.5. Akt is a key molecule for cardiac hypertrophy
Akt is the best-characterized molecule in the downstream pathways
of IGF-1R and IR signaling. It is involved in diverse cellular processes, in-
cluding the regulation of cell growth, survival, metabolism, and angio-
genesis. Akt promotes cardiac hypertrophy via modulation of several
signaling pathways. Eukaryotic translation initiation factor 4E-binding
protein 1(4E-BP1) inhibits the initiation of translation and is negatively
regulated by mTOR, while PI3K-Akt-mTOR signaling suppresses 4E-BP1
and promotes compensatory cardiac hypertrophy. Specific depletion of
mTOR in the heart inhibits the protective hypertrophic response and
promotes cardiac dysfunction during pressure overload [64]. Akt sup-
presses CCAAT/enhanced-binding protein (C/EBP)β and upregulates
Cbp/p300-interacting transactivator with ED-rich carboxy-terminal do-
main 4 (CITED4), which is negatively regulated by C/EBPβ. CITED4 in-
creases the expression of GATA4 and promotes cardiac hypertrophy.
Systemic heterozygous C/EBPβ depletion promotes physiological cardi-
ac hypertrophy, ameliorates systolic dysfunction, and increases the sur-
vival rate in a murine model of left ventricular pressure overload [65].
Activation of Akt initially promotes growth of the heart while preserv-
ing cardiac function [66–68], but constitutive activation of this signaling
pathway leads to pathological hypertrophy and cardiac dysfunction
[19]. Mice that are transgenic for PI3K, IGF-1, or IGF-1R and mice sub-
jected to exercise training show increased Akt expression (by 4-fold,
6-fold, 6-fold, and 1.5- to 2-fold, respectively), and cardiac dysfunction
does not occur within this Akt expression range [22,69–71]. However,
forced expression of Akt in cardiac tissue for 6 weeks (a 15-fold increase
compared with normal littermates) caused pathological hypertrophy
and cardiac dysfunction [19], while enhancement of cardiac Akt signal-
ing promoted pathological hypertrophy associated with progressive
249
suppression of mitochondrial fatty acid oxidation [72]. Androgens
such as testosterone promote cardiac hypertrophy and heart failure.
Anti-androgen therapy was shown to suppress Akt-mTOR signaling
and attenuate cardiac hypertrophy and left ventricular dysfunction in
a model of left ventricular pressure overload [73]. In a murine pressure
overload model, heterozygous depletion of Akt significantly attenuated
cardiomyocyte hypertrophy and improved cardiac dysfunction [1]. Al-
though it is widely accepted that Akt is the critical regulator coordinat-
ing angiogenesis and physiological growth of the myocardium, there is
accumulating evidence that excessive Akt signaling has a pathological
effect under some circumstances by promoting dysregulated cardiac
hypertrophy that results in tissue hypoxia and contributes to the pro-
gression of heart failure.
4.6. Role of sirtuins in modulating Akt signaling
Sirtuins (silent mating type information regulation 2 homologs)
have recently received considerable attention because of their role in
aging. Calorie restriction is the best established method of increasing
longevity in various models ranging from Caenorhabditis elegans to
mice, and the levels of SIRTs 1, 3, and 6 are reported to be increased
by calorie restriction [74–77]. It is generally accepted that SIRT3 and
SIRT6 are involved in regulation of the aging process in mammals [78–
81]. SIRT3 and SIRT6 were recently reported to inhibit cardiac hypertro-
phy. SIRT3 null mice develop cardiac hypertrophy with cardiac dysfunc-
tion, while overexpression of SIRT3 in the heart attenuates agonist-
induced cardiac hypertrophy [82]. Inhibition of SIRT3 expression or sup-
pression of SIRT3 activity is associated with an increase of reactive oxy-
gen species (ROS) and activation of Akt signaling [82,83]. Moreover,
specific overexpression of SIRT6 in the heart inhibits cardiac hypertro-
phy induced by agonists or pressure overload, and this anti-hypertro-
phic effect of SIRT6 is mediated via inhibition of IGF-1/Akt signaling
[84] (Fig. 1). SIRT6 interacts with c-Jun, resulting in deacetylation of his-
tone H3K9, and thus inhibits Akt expression at the transcriptional level.
The role of SIRT1 in cardiac hypertrophy is complex. Marked eleva-
tion of SIRT1 expression (12.5-fold) induces pathological hypertrophy
associated with cardiac dysfunction, whereas less marked induction
(7.5-fold) attenuates age-related cardiac hypertrophy [85]. In addition,
haploinsufficiency of SIRT1 attenuates cardiac hypertrophy due to pres-
sure overload, while SIRT1 overexpression has a detrimental effect in
pressure overload models [86]. SIRT1 deacetylates Akt and thus pro-
motes its binding to phosphoinositide-3,4,5 triphosphate and subse-
quent activation. Both SIRT1 and Akt stimulate endothelial cell
proliferation, differentiation, and migration, a process known as
sprouting and branching. Neovascularization is suppressed in SIRT-1
null mice, while SIRT-1 deficient zebrafish display dysregulation of en-
dothelial sprouting and develop malformations of the vascular network
[87]. Further studies are needed to elucidate the role of SIRT1 in coordi-
nating cardiac angiogenesis and hypertrophy.
5. Mechanisms of pathological cardiac hypertrophy
Enlargement of the heart in response to hypertensive stress, myo-
cardial injury, or excessive neurohumoral activation is associated with
cardiac dysfunction and is described as “pathological hypertrophy”
[88]. Cardiac function is initially maintained in pressure overload-in-
duced cardiac hypertrophy, and this is described as the adaptive
phase. However, sustained pressure overload promotes the transition
from the adaptive to maladaptive phase, which is characterized by a re-
duced ejection fraction and left ventricular dilatation. Ventricular wall
stress is proportional to both the left ventricular (LV) cavity radius
and LV pressure, while it is inversely proportional to LV wall thickness
[17,89]. For this reason, the initial stages of pressure overload hypertro-
phy are described as “compensatory”, and were thought to be beneficial.
However, LV hypertrophy has been reported as an independent risk fac-
tor for adverse cardiovascular events, such as heart failure and
250 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
arrhythmia [90,91]. Furthermore, data from both clinical and basic stud-
ies indicate that cardiac function can be maintained by therapy
targeting suppression of LV hypertrophy in the setting of hemodynamic
stress [92–94]. These findings have led to rethinking of the role of cardi-
ac hypertrophy under these conditions and it has been suggested that
heart failure can be treated through modulation of cardiac hypertrophy
induced by stress [95,96].
In the process of hypertrophic remodeling, it is widely accepted that
the nature of the stress determines the phenotype. Thus, intermittent
pressure overload induces diastolic dysfunction and vascular rarefaction
before cardiac hypertrophy, unlike the changes in exercise models
employing swimming or running [97]. Pathological cardiac hypertrophy
is usually associated with increased rates of myocytes death and fibrotic
remodeling, that would promote systolic and diastolic dysfunction, gen-
erally predisposing to the development of heart failure. The activation of
mechanotransduction and neurohormonal mechanisms are the initial
step that drives pathological hypertrophy preceding heart failure. Pro-
teins acting as mechanotransducers are crucial for physiological hyper-
trophy and dysregulation of this system promotes pathological
hypertrophy [11]. Adrenergic nervous system and renin-angiotensin
system are extensively studied neurohormonal mechanisms, initially
activated upon stress to increase contractility and survival in the early
phase, and become pathological in the chronic phase. The β-adrenergic
receptor blockers, angiotensin-converting enzyme inhibitors and angio-
tensin receptor blockers are well accepted to reduce left ventricular
mass and contribute for favorable clinical outcome in patients with
heart failure. Different signaling members are proposed to mediate car-
diac hypertrophy, and several molecules are reported to be involved in
pathogenic signaling pathways and these are discussed next.
5.1. Calcineurin-nuclear factor of activated T cells (NFAT) signaling
Both physiological and pathological cardiac hypertrophy are associ-
ated with elevation of cardiomyocyte Ca2+ levels. Ca2+ modulates the
activity of various Ca2+-dependent signaling pathways, including cal-
cineurin/nuclear factor of activated T cells (NFAT) signaling and cal-
modulin-dependent kinase II signaling. Neurohumoral mediators such
as catecholamines and angiotensin II bind to seven-transmembrane re-
ceptors that are coupled to G proteins. Gq signaling activates phospho-
lipase C (PLC), and this catalyses the synthesis of inositol 1,4,5-
Fig. 2. Signaling pathways for pathological cardiac hypertrophy. Neurohumoral factors, such as catecholamines or angiotensin II, upregulate calcineurin/NFAT and CaMKII/MEF-2 signaling
to induce pathological cardiac hypertrophy. IL-6/gp130/JAK/STAT signaling also promotes pathological hypertrophy. Nitric oxide and natriuretic peptide-coupled/cGMP/PKG signaling is
anti-hypertrophic, while PDE5 and PDE9A promote pathological cardiac hypertrophy by suppressing this signaling pathway.
triphosphate (Ins(1,4,5) P3), which induces intracellular Ca2+ release
and activation of calcineurin/NFAT signaling [13,98]. Calcineurin is a
Ca2+-activated serine-threonine protein phosphatase that dephosphor-
ylates NFAT in the cytoplasm, inducing its nuclear translocation and the
expression of genes involved in hypertrophy. Activation of calcineurin/
NFAT signaling alone is sufficient to induce pathological cardiac hyper-
trophy [99–101] (Fig. 2). In contrast, physiological cardiac hypertrophy
induced by exercise or pregnancy is not associated with increased cal-
cineurin/NFAT signaling [102]. Recently, transient receptor potential
cation (TRPC) channels were reported to be involved in activation of cal-
cineurin/NFAT signaling. TRPC channels regulate the movement of Ca2+
and Na+ in specific microdomains, and expression of these channels
was reported to be increased along with activation in pathological hy-
pertrophy or heart failure [103–106]. TRPC1, TRPC3, and TRPC6 are
the best known of several isoforms, and inhibition of the gene expres-
sion of these isoforms attenuates cardiac hypertrophy induced by ago-
nists and pressure overload [103,107].
5.2. β-adrenergic receptor signaling and Ca2+/calmodulin-dependent ki-
nase II signaling
Patients with heart failure have high blood catecholamine levels and
increased adrenergic tone is correlated with a poor clinical outcome
[108]. High adrenergic activity is associated with cardiac hypertrophy,
and the basal plasma norepinephrine concentration was shown to pre-
dict the extent of cardiac hypertrophy in hypertensive patients inde-
pendently of systolic blood pressure and body mass index [109]. It
was initially considered that β-blockers were contraindicated for pa-
tients with heart failure, but these drugs later became first-line therapy
for severe heart failure based on data from a number of large-scale clin-
ical trials [110,111]. Calmodulin-dependent kinase II (CaMKII) is a ser-
ine/threonine kinase that is regulated by the Ca2 +/calmodulin
complex, ROS, and exchange proteins directly activated by cAMP
(EPAC). Catecholamines bind to adrenergic receptors, which are classi-
fied as G-protein-coupled receptors, and signaling via these receptors
activates CaMKII. Activation of the renin-angiotensin-aldosterone sys-
tem increases the angiotensin II level, and directly induces cardiac hy-
pertrophy via activation of CaMKII signaling.
Studies performed in humans and rodents have shown that cardiac
CaMKII activity is increased in heart failure. Gain of CaMKII function
 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
leads to cardiac hypertrophy, while inhibition of CaMKII ameliorates
myocardial hypertrophy and improves heart failure [112–115]. There
are four isoforms of CaMKII encoded by different genes (α, β, γ and δ).
Each isoform has a different tissue distribution and CaMKIIδ is the
major isoform in the myocardium. CaMKIIδ null mice showed less
prominent cardiac hypertrophy in response to pressure overload
along with amelioration of systolic dysfunction and a higher survival
rate [116,117]. Activation of Gq/PLC/IP3 signaling by norepinephrine,
phenylephrine, or endothelin-1 induces the growth of neonatal rat ven-
tricular myocytes, along with elevated expression of fetal genes such as
those encoding atrial natriuretic peptide (ANP), brain natriuretic pep-
tide (BNP), myosin light chain-2, or α and β-myosin heavy chain. Forced
expression of CaMKII results in the same phenotypic changes as induc-
tion of neurohumoral agonist/Gq signaling, while pharmacological inhi-
bition of CaMKII suppresses such negative remodeling [118–120].
CaMKII induces cardiomyocyte growth via phosphorylation of class II
histone deacetylases (HDACs), especially HDAC4 and HDAC5, by pro-
moting the export of these molecules from the nucleus, leading to dere-
pression of MEF-2-mediated gene expression and cardiac hypertrophy
[115,121–123]. In short, activation of CaMKII is sufficient to induce
pathological cardiac hypertrophy (Fig. 2).
5.3. cGMP/protein kinase G signaling
Nitric oxide (NO) and natriuretic peptide-coupled signaling is medi-
ated by a second messenger, cyclic guanosine monophosphate (cGMP).
cGMP is involved in regulating physiological processes in the myocardi-
um, including cell growth and apoptosis, and activation of cGMP/pro-
tein kinase G (PKG) signaling is reported to inhibit cardiac
hypertrophy [124]. Phosphodiesterases (PDEs) specifically cleave the
3′,5′-cyclic phosphate moiety of cyclic adenosine monophosphate
(cAMP) and/or cGMP. At least 21 PDE genes have been cloned and clas-
sified into 11 families. Among them, PDE-5, PDE-6, and PDE-9 specifical-
ly act on cGMP; PDE-4, PDE-7, and PDE-8 are specific for cAMP; and
PDE-1, PDE-2, PDE-3, PDE-10, and PDE-11 interact with both cAMP
and cGMP [125]. Activity of both cGMP and PKG is reduced in patients
with heart failure [126]. There is evidence that a PDE-5 inhibitor has
an anti-hypertrophic effect in the setting of pressure overload, which
is associated with activation of PKG and its target molecule, regulator
of G protein signaling 2 (RGS2), and with suppression of TRPC6/calcine-
urin/NFAT signaling [127,128]. Recently, cGMP-selective PDE9A was de-
tected in mammalian hearts and was reported to contribute to
suppression of cGMP signaling, thereby promoting cardiac hypertrophy
and remodeling [129] (Fig. 2).
5.4. Protein kinase C and mitogen-activated protein kinase signaling
The α-adrenergic receptors (α-ARs) couple with Gq, and Gq-protein
kinase C (PKC) signaling and mitogen-activated protein kinase (MAPK)
signaling promote cardiac hypertrophy in mice, while suppression of
PKC conversely inhibits GPCR-mediated cardiac hypertrophy [130,131].
MAPK signaling has an important role in the regulation of cell prolif-
eration, cell growth, and stress responses. It is induced in
cardiomyocytes by small G proteins (Ras, Rac, Rho, etc.), G-protein-
coupled receptors, and stress, and is followed by several levels of phos-
phorylation-based amplification. There are three main branches of
MAPK signaling, which are p38MAPK, c-Jun N-terminal kinases
(JNKs), and extracellular signal-regulated kinase (ERK)1/2. The mito-
gen-activated protein kinase kinase (MKK)1/2/ERK1/2/NFAT signaling,
MKK 4/7/JNKs/MEF2 signaling, and MKK3/6/p38MAPK/GATA4 signal-
ing pathways are involved in modulation of cardiac hypertrophy. Nearly
all of the MAPK signaling components are activated in end-stage heart
failure in humans and in animal models of pathological cardiac hyper-
trophy [132–134]. It is generally considered that the ERK1/2 signaling
pathway is pro-hypertrophic. Forced expression of MKK1 induces phys-
iological cardiac hypertrophy with cardiomyocyte growth via activation
251
of the MKK1/ERK1/2 pathway, and also protects against cell death [135],
while deletion of ERK (Erk1–/– and Erk2+/–) does not attenuate the hy-
pertrophic response to various stimuli [136]. These results indicate
that ERK1/2 signaling is pro-hypertrophic, but is not essential for the de-
velopment of cardiac hypertrophy. It was recently reported that the
ERK1/2 signaling pathway coordinates eccentric and concentric growth
of the heart. Mice with complete cardiac deletion of ERK1/2 (Erk1–/–
MHC-Cre Erk2fl/fl) developed eccentric cardiac hypertrophy (lengthen-
ing) and systolic dysfunction in response to pressure overload or stimu-
lation with angiotensin II/phenylephrine, while Mkk1 transgenic mice
showed concentric growth (wall thickening) of the heart [137]. Al-
though p38MAPK signaling is generally accepted to be pathological, its
role in promoting cardiac hypertrophy is puzzling and still controver-
sial. Activation of MKK6-p38MAPK signaling induces hypertrophy,
whereas activation of MKK3 signaling promotes apoptosis in isolated
neonatal cardiomyocytes. In contrast, studies in mouse models have in-
dicated that p38MAPK does not induce hypertrophy, but plays a role in
regulating apoptosis, fibrosis, and left ventricular dilatation [138].
Forced activation of cardiac MKK3-p38MAPK signaling leads to dilated
cardiomyopathy with early death, while activation of MKK6-p38MAPK
signaling results in restrictive cardiomyopathy and early death. Howev-
er, left ventricular hypertrophy does not develop in either of these
models [139]. JNK mainly has an anti-hypertrophic effect and is report-
ed to repress cardiac hypertrophy through inhibition of calcineurin/
NFAT signaling [140]. MKK4 is a positive regulator of JNK and a key me-
diator that prevents the transition from an adaptive response to mal-
adaptive cardiac hypertrophy through modulation of calcineurin/NFAT
signaling [141].
MAPK phosphatase 1 (MKP-1) is a negative feedback inhibitor of
MAPK signaling, and constitutive expression of MKP-1 in the heart
downregulates p38MAPK, JNK1/2, and ERK1/2, and also prevents induc-
tion of hypertrophy by catecholamines or aortic banding [142]. Recent-
ly, dual-specificity phosphatases 1 and 4 (Dusp1 and 4, also known as
MKP-1 and 4, respectively) were reported to have a cardioprotective
role through inhibition of p38MAPK. Dusp1 and 4 null mice show eleva-
tion of p38MAPK with no change of JNK or ERK1/2 levels, and have a low
survival rate associated with systolic dysfunction and cardiac dilatation
[143].
5.5. Insulin/insulin receptor (IR)/Akt signaling—as a pathway mediating
pathological hypertrophy
It is widely accepted that insulin signaling pathway is essential in
promoting physiological hypertrophy, however, accumulating evidence
has indicated that insulin/insulin receptor (IR)/Akt signaling should be
maintained within a physiological range to become beneficial. Animal
studies and large-scale clinical trials have not provided conclusive evi-
dence about whether insulin signaling is cardioprotective in adults.
Complete suppression of insulin signaling is detrimental through inhibi-
tion of physiological hypertrophy, while overactivation of this signaling
pathway induces pathological cardiac hypertrophy and disturbs ho-
meostasis. Chronic hyperinsulinemia induces pathological hypertrophy
by promoting angiotensin II signaling [144]. Also, intensive glycemic
control with insulin did not reduce cardiovascular events in diabetic pa-
tients, but instead was associated with an increase of events [145]. In a
murine model of chronic pressure overload, cardiac insulin signaling
was markedly increased and mismatch developed between cardiomyo-
cyte size and vascularity, inducing myocardial hypoxia, cardiomyocyte
death, and cardiac dysfunction. Conversely, inhibition of cardiac insulin
signaling by heterozygous Ir deletion in the heart or whole body hetero-
zygous Akt deletion significantly attenuated cardiomyocyte hypertro-
phy and improved cardiac dysfunction due to pressure overload.
These findings suggest that sustained activation of cardiac insulin sig-
naling causes myocardial hypoxia and systolic dysfunction when the
heart is subjected to pressure overload [1]. Kemi et al. have shown
that Akt-mTOR signaling is increased with physiological cardiac
252 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
hypertrophy upon exercise, in contrast, they also showed that this sig-
naling pathway is reduced with pathological hypertrophy in a murine
LV-pressure overload model. This report indicates that Akt-mTOR sig-
naling may diverge physiological from pathological hypertrophy [57].
Ras homology enriched in brain (Rheb) is the positive regulator for
mTOR, and Rheb-mTOR signaling was shown to be activated in the
heart upon metabolic stress, especially in a cardiac ischemia model,
and promote myocardial damage via the suppression of autophagy
[146]. Systemic insulin resistance is prevalent among patients with sys-
tolic dysfunction and it has been reported to increase the future risk of
heart failure [147–149]. Although several lines of evidence have sug-
gested a link between heart failure and systemic metabolic dysfunction,
the underlying molecular mechanisms and clinical implications have
been unclear. Recently, pressure overload was shown to induce adipose
tissue inflammation by promoting lipolysis, leading to systemic meta-
bolic dysfunction. It was also demonstrated that suppression of adipose
tissue inflammation improved systemic insulin resistance
(hyperinsulinemia) and ameliorated cardiac dysfunction induced by
chronic pressure overload, possibly via suppression of excessive cardiac
insulin signaling [1,150]. These results indicate that insulin signaling
also needs to be regulated within a certain physiological range to main-
tain homeostasis, with too much or too little signaling via the IR being
detrimental (Fig.1).
6. Modifiers of cardiac hypertrophy
6.1. Endogenous factors
6.1.1. Autophagy
Autophagy is an evolutionary conserved catabolic system involved
in degradation of unnecessary or dysfunctional cellular components
through lysosomal machinery, thus recycling amino acids for the syn-
thesis of proteins that are essential for cell survival. Autophagy is acti-
vated by various stresses, including starvation, ischemia-reperfusion,
infection, ROS, and hypoxia [151]. A basal level of autophagy is essential
for removal and renewal of dysfunctional mitochondria and for main-
taining cellular homeostasis. The role of stress-induced autophagy has
yet to be completely defined, although it is known to promote or atten-
uate pathology in several disease models [152–154]. An increase of the
autophagic response is protective during cardiac ischemia [155], but ac-
tivation of autophagy is associated with deterioration of cardiac func-
tion in a pressure overload model [156] or an ischemia-reperfusion
model [155]. There is accumulating evidence that autophagy has a role
in cardiac hypertrophy. Autophagy protein 5 (encoded by Atg5) is the
key molecule in formation of autophagic vesicles. In adult mice, cardi-
ac-specific deletion of Atg5 was reported to induce cardiac hypertrophy,
systolic dysfunction, and left ventricular dilatation [157]. Charged
multivesicular body protein 2B (CHMP2B) regulates the fusion of
autophagosomes and lysosomes, and therefore is essential for autopha-
gy. Atrogin-1 degrades CHMP2B and maintains it at a physiological level.
Whole body deletion of atrogin-1 leads to a marked increase of
CHMP2B, along with suppression of the autophagic response in cardiac
tissue and significant cardiac hypertrophy at the age of 16 months.
While systolic cardiac dysfunction does not develop, there is significant
reduction of the lifespan, possibly due to diastolic dysfunction induced
by cardiac fibrosis [158]. Another study showed that heterozygous dele-
tion of Becn1 (the gene coding for Beclin-1 that is involved in early
autophagosome formation) inhibits autophagy in cardiomyocytes and
ameliorates pathological remodeling caused by pressure overload. In
contrast, forced expression of Becn1 upregulates autophagic responses
and promotes pathological cardiac remodeling [156]. These results indi-
cate that autophagic responses are critically involved in maintaining ho-
meostasis in response to cardiac stress, with the pathological effects of
inhibiting autophagy being dependent on the animal model, extent of
induction, and timing of observation.
6.1.2. Modification of DNA and histones
Distinct families of DNA elements described as promoters and en-
hancers regulate gene transcription. By modulating the structure of
chromatin, epigenetic modifications regulate the access of promoters
and enhancers to DNA and thus control gene expression. Acetylation
of histones on lysine residues promotes the relaxation of chromatin,
leading to transcriptional activation, while suppression of histone acet-
ylation leads to condensation of chromatin and inhibition of gene ex-
pression. Active promoters are characterized by high levels of
monoacetylated lysine 9 and lysine 14 (H3K9ac and H3K14ac) and
trimethylated (me3) lysine 4 (H3K4me3) on histone H3. Inactive pro-
moters are characterized by methylated DNA, trimethylation of lysine
9 and lysine 27 on histone H3 (H3K9me3 and H3K27me3), and
deacetylation of histones. Active enhancers are enriched in H3K27ac,
while lack of H3K27ac and a high level of H3K27me3 define an enhancer
as “poised”.
Acetylation of histones is regulated by histone acetyltransferases
(HATs) and histone deacetylases (HDACs). Overactivation of HATs,
such as CREB-binding protein (CBP) and p300, induces hypertrophy
and left ventricular remodeling in mice [159,160]. Hypertrophy of
non-necrotic tissue in a myocardial infarction model also requires
p300 HAT activity [161], and phenylephrine-induced cardiac hypertro-
phy is associated with high p300 activity. HDACs have an opposing
role to HATs by mediating the removal of acetyl groups. There are
three main classes of HDACs, which are class I (HDAC1, 2, 3, and 8),
class II (HDAC4, 5, 6, 7, 9, and 10), and class III. Class II HDACs have an
anti-hypertrophic effect [162]. In mice, depletion of HDAC5 or HDAC9
was reported to increase sensitivity to stress signals and enhance cardi-
ac hypertrophy, owing to the role of these enzymes in silencing MEF2C
[163]. Recently, an increased load on the heart was shown to induce nu-
clear export of HDAC4, demethylation of H3K9, and activation of ANP,
with these responses not requiring an increase of histone acetylation
[164]. Unlike class II HDACs, the class I HDACs mediate hypertrophic re-
sponses. HDAC2 induces cardiac hypertrophy by repression of INPP5F,
the gene coding for phosphatidylinositide phosphatase SAC2, which is
a negative regulator of the Akt/GSK-3β pathway [165]. Similar to class
II HDACs, class III HDACs are associated with inhibition of cardiac hyper-
trophy and with improved cardiomyocyte survival. Modulation of
HDAC expression, including suppression of specific pro-hypertrophic
HDACs, has the potential to become next-generation therapy for heart
failure.
Methylation of cytosine on DNA induces the repression of transcrip-
tion. Three DNA methyltransferases (DNMTs) have been identified in
mammals (DNMT1, 3A, 3B). The epigenetic profile undergoes alter-
ations in end-stage cardiomyopathy. Increased expression of certain
genes in the failing heart is associated with promoter demethylation,
but hypermethylation does not show a clear correlation with reduced
gene expression [166]. Significant hypomethylation at satellite regions
has also been found in failing hearts, and is correlated with a 27-fold in-
crease of the corresponding transcripts [167]. Accordingly, further stud-
ies are warranted to determine the role of alterations of DNA
methylation in the progression of heart failure.
6.1.3. MicroRNA
MicroRNA (miRNA) is a class of small non-coding RNAs involved in
repression of translation or transcriptional degradation of target
mRNAs and Mirbase lists N 2000 known human miRNAs [168]. A single
miRNA may have tens to hundreds of target genes and there is accumu-
lating evidence that miRNAs have a role in cardiac development, hyper-
trophy, and failure. In mice with left ventricular pressure overload or
calcineurin overexpression, 11 miRNAs showed upregulation, and five
of them were also increased in the failing human heart [169]. Forced ex-
pression of these five miRNAs (miR-23a, miR-23b, miR-24, miR-195 and
miR-214Z) induced hypertrophy of primary cultured cardiomyocytes
[169,170]. In addition, overexpression of miR-212/132 in
cardiomyocytes induced pathological cardiac hypertrophy and heart
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failure in mice. Conversely, cardiac hypertrophy and systolic dysfunc-
tion due to pressure overload were significantly ameliorated in miR-
212/132 null mice. FoxO3 is a transcriptional molecule involved in
anti-hypertrophic and pro-autophagic responses. It is located down-
stream of (and is negatively regulated by) the insulin signaling path-
way, with activation of insulin signaling promoting translocation of
FoxO3 from the nucleus and inhibiting its activity. Both miR-212 and
miR-132 were reported to directly inhibit FoxO3 expression and induce
pathological hypertrophy via upregulation of calcineurin/NFAT signal-
ing and suppression of autophagy [170], while cardiomyocyte-specific
overexpression of miR-208a induced pathological hypertrophy associ-
ated with cardiac dysfunction [171]. Moreover, miR-22 is reported to
be increased in the failing human heart [172]. Stimulation by angioten-
sin II or phenylephrine increases miR-22 expression in cultured
cardiomyocytes along with enlargement of cardiomyocytes, while sup-
pression of miR-22 ameliorates angiotensin II- or phenylephrine-in-
duced cardiomyocyte hypertrophy [173]. However, in vivo deletion of
miR-22 leads to cardiac dilatation and contractile dysfunction associat-
ed with reduction of SERCA2a pump activity [174]. Several other
miRNAs are also involved in promotion or suppression of cardiac hyper-
trophy and the details were recently reviewed elsewhere [175,176].
6.1.4. Metabolism
Heart weight and myocyte fiber size are reduced by starvation or se-
vere weight loss. Heart size is increased in obesity without hypertension
or other cardiovascular and/or metabolic abnormalities, while modest
weight loss is associated with reduction of heart size without hemody-
namic changes in normotensive obese subjects. Thus, it is highly possi-
ble that there are mechanisms which link heart size to the systemic
nutritional status.
The heart requires a huge amount of ATP to allow it to continuously
pump blood. Under physiological conditions, more than 95% of the ATP
utilized in the heart is generated by oxidative phosphorylation, with
most of the remainder coming from glycolysis (5%) and to a lesser ex-
tent from the Krebs cycle. Between 60 and 70% of the ATP generated is
used for cardiac contraction and the remaining 30–40% is consumed
by various ion pumps. Approximately 70−90% of cardiac ATP originates
from oxidation of fatty acids (FAs), while the remaining 10–30% is pro-
duced by oxidation of glucose, lactate, and ketone bodies [177]. During
glycolysis, glucose is converted into pyruvate and this is subsequently
converted to lactate or oxidized in the mitochondria. It is generally ac-
cepted that utilization of FAs is impaired in the failing heart. FA uptake
is reduced in models of heart failure induced by rapid pacing and a
high-salt diet [178,179], and FA transporter activity is reduced when
systolic function is impaired [179–182]. In some models, enzymes in-
volved in FA oxidation and the FA oxidation rate are decreased in the
early (compensated) phase of left ventricular hypertrophy [180,183],
while this occurs during the late phase along with cardiac dysfunction
in other models [182]. It was thought that FA overload developed in
the failing heart, promoting oxidative stress derived from toxic lipid de-
rivatives [184], but studies based on pharmacological inhibition of car-
diac FA have challenged this concept. In mice fed a high fat diet,
myocardial insulin resistance developed and promoted left ventricular
remodeling in response to pressure overload [185]. Another study
showed reduction of cardiac hypertrophy and improvement of cardiac
function after maintaining Dahl salt-sensitive rats on a high fat diet
[186], while acute suppression of FA oxidation led to significant worsen-
ing of systolic function in patients with end-stage heart failure [187].
Therefore, additional investigation of the role of FA metabolism in
heart failure is required to elucidate the therapeutic potential of modu-
lating FA metabolism.
FA and glucose negatively regulate each other, so that use of one
substrate directly inhibits use of the other (the Randle cycle) [188]. In
the physiological state, the heart predominantly generates ATP from
fatty acids, but progression of heart failure promotes utilization of glu-
cose and the heart eventually becomes unable to utilize either substrate
253
in end-stage failure [189]. In rats with abdominal aortic constriction and
compensated cardiac hypertrophy, glycolysis increases without oxida-
tion of glucose [190]. In rat LV-pressure overload model generated
with clipping of ascending aorta, total lactate production per gram left
ventricular weights was higher in hypertrophied hearts than non-
hypertrophied controls when evaluated 11–12 weeks after the opera-
tion [191]. In another rat LV-pressure overload model due to aortic
arch constriction, it was reported that cardiac oxidation of glucose in-
creased initially during the phase of compensated hypertrophy, follow-
ed by a decrease after the onset of systolic dysfunction [180]. In mice
with LV-pressure overload, glucose oxidation, glycolysis and lactate ox-
idation were reduced 6 weeks after the operation [192]. Interestingly,
spontaneously hypertensive rats show higher glucose oxidation rates
in the phase of hypertrophy before cardiac dysfunction occurs [193].
On the other hand, glucose oxidation is unchanged in rats with myocar-
dial infarction, despite the development of systolic dysfunction [194],
while patients with idiopathic dilated cardiomyopathy show increased
total glucose utilization [195]. These findings suggest that changes of
glucose utilization depend on the pathogenesis and stage of heart failure
[177].
Glucose is transported into the cytosol by glucose transporters
(GLUTs), with GLUT1 being the major transporter in the fetal heart
and GLUT4 having this role in the adult heart. Modulating GLUT1 or
GLUT4 expression was reported to regulate hypertrophy. Deletion of
GLUT1 in cardiomyocytes did not alter cardiac hypertrophy, fibrosis,
or capillary rarefaction in response to pressure overload. Although
GLUT1 depletion reduced glycolysis and glucose oxidation by 50%,
with a reciprocal increase of FA oxidation, there was no exacerbation
of systolic dysfunction [196]. Forced expression of GLUT1 in cardiac tis-
sue attenuated pathological remodeling due to left ventricular pressure
overload, but promoted cardiac hypertrophy and failed to prevent sys-
tolic dysfunction [197]. Cardiomyocyte-specific deletion of GLUT4 in-
duces cardiomyocyte hypertrophy with increased expression of ANP
and BNP in the ventricles. Myocardial fibrosis does not develop, and
both basal and isoproterenol-induced contraction is preserved,
representing the compensated phase of cardiac hypertrophy [198].
Under hypoxic conditions, oxidation of glucose is generally considered
to be a protective response that generates ATP, but switching from FA
to glucose was reported to activate mTOR signaling and promote cardiac
hypertrophy [199].
It was recently reported that fructose metabolism is elevated in the
failing heart and contributes to the progression of cardiac hypertrophy.
Hypoxia inducible factor-1α (HIf-1α) increases the expression of splice
factor 3b subunit 1 (SF3B1) and mediates alternative splicing of
ketohexokinase (KHK) pre-mRNA. Splice switching of KHK-A to KHK-
C promotes fructolysis and induces cardiac hypertrophy by upregula-
tion of lipid and protein biosynthesis. Depletion of SF3B1 suppressed
cardiac hypertrophy in a murine model of left ventricular pressure over-
load, and SF3B1 was markedly increased in patients with hypertrophic
cardiomyopathy and aortic stenosis [200]. These results suggest that in-
hibition of the SF3B1- KHK-C axis and modulation of fructolysis could
potentially be new targets for treating heart failure, but more investiga-
tions are required to define the pathological link between metabolic
dysfunction and cardiac hypertrophy.
6.2. Exogenous factors
6.2.1. Fibroblasts
Fibroblasts account for 27% of all cardiac cells in mice and 64% in rats,
while non-cardiomyocytes (mainly fibroblasts) account for 72% of total
cells in humans [201,202]. Thus, fibroblasts are one of the chief cell
types in cardiac tissue, contributing to maintenance of homeostasis
under physiological conditions and to tissue remodeling in response
to stress. Cardiac fibroblasts express extracellular matrix (ECM) recep-
tors coupling mechanical stimuli to functional responses, and are critical
regulators of the composition and stiffness of the ECM and fibrotic
254 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
response [203,204]. Myocardial fibrosis and stiffness is an important
component of diastolic dysfunction. Mechanical stress activates cardiac
fibroblasts and promotes the production and release of bioactive medi-
ators [205]. Cardiac fibroblasts originate from several sources, including
resident fibroblasts, bone marrow progenitors, and endothelial cells.
Pressure overload induces rapid expansion of resident fibroblasts origi-
nating from the epicardium and endocardium, rather than fibroblasts
derived from hematopoietic precursors [206]. The role of cardiac fibro-
blasts in cardiac hypertrophy is not yet clearly defined, partly due to
the lack of fibroblast-specific genes. Several Cre systems (including
Fsp1-Cre, Postn-Cre, Tcf21-Cre, Col1a1-Cre, and Col1a2-Cre) have been
created to specifically deplete target genes in fibroblasts. Some of
these systems were found to be nonspecific under physiological or path-
ological conditions, however, accumulating evidence indicates that fi-
broblasts communicate with cardiomyocytes by secreting humoral
mediators such as IGF-1, fibroblast growth factor-2 (FGF-2),
transforming growth factor-β1 (TGF-β1), interleukin-33(IL-33) in an
autocrine and paracrine manner. Krüppel-like factor 5 was recently re-
ported to have a critical influence on cardiac function through regula-
tion of fibroblasts. In a fibroblast Klf5 deletion model generated by
crossing Postn-Cre mice with Klf5flox/flox mice, cardiac hypertrophy
and fibrosis due to pressure overload were both attenuated. Interesting-
ly, Postn-Cre Klf5flox/flox mice subjected to severe pressure overload also
showed amelioration of cardiac hypertrophy and fibrosis, despite signif-
icant cardiac dysfunction along with increased mortality. IGF-1 expres-
sion was transactivated by Klf5 in fibroblasts and this promoted
cardiomyocyte hypertrophy contributing for the suppression of cardiac
dysfunction [42]. Fibroblast growth factor-2 (FGF-2) is predominantly
expressed by cardiac fibroblasts and induces cardiac hypertrophy by
the activation of mitogen-activated protein kinase signaling [207,208].
Hypertrophic response in cardiomyocytes is significantly attenuated in
FGF-2 null mice in a murine LV pressure overload model [209]. Cardiac
fibroblasts are also the main source for the production of connective tis-
sue growth factor (CTGF). In cultured cardiomyocytes, CTGF induced
cardiomyocyte hypertrophy by activating Akt signaling [210]. Forced
expression of CTGF was shown to promote age-dependent cardiac hy-
pertrophy and dilatation [211]. Recently, fibroblast-derived microRNA
21 (miR-21) was reported to promote cardiomyocyte hypertrophy,
while pharmacological inhibition of miR-21 ameliorated the hypertro-
phic response to angiotensin II [212]. TGF-β is secreted by cardiac fibro-
blasts, cardiomyocytes and endothelial cells. TGF-β/Smad3 signaling is
described as canonical pathway, contributing for the progression of car-
diac fibrosis. Neutralization of TGF-β in a rat LV pressure-overload
model attenuated fibroblast activation and collagen mRNA expression,
but did not affect cardiac hypertrophy [213]. Another study showed
that the inhibition of TGF-β reduces non-myocyte proliferation and at-
tenuate cardiac hypertrophy in a murine hypertrophic cardiomyopathy
model [214]. TGF-β/TGF-β activated kinase 1(TAK1) signaling is de-
scribed as non-canonical pathway, and in addition to its contribution
for promoting fibrosis, it is reported to enhance cardiac hypertrophy.
TAK1 is activated upon LV pressure-overload and forced expression of
TAK1 induced cardiac hypertrophy and heart failure [215]. Conversely,
dominant negative form of TAK1 attenuated TGF-β induced cardiomyo-
cyte hypertrophy [216]. These results suggest that the suppression of
TGF-β/TAK1 signaling would become anti-fibrotic and anti-hypertro-
phic therapy in heart failure [203]. Fibroblasts are reported to secrete
anti-hypertrophic factors. Adrenomedullin is secreted by cardiac fibro-
blasts, cardiomyocytes and endothelial cells and suppress cardiomyo-
cyte hypertrophy [217]. Adrenomedullin loss of function murine
model exhibit marked cardiac hypertrophy and fibrosis in response to
aortic constriction [218]. IL-33 is predominantly produced in cardiac fi-
broblasts upon mechanical stress and suppresses cardiac hypertrophy
induced by AngII, phenylephrine or LV pressure overload [219]. Taken
together, these results indicate that fibroblasts can directly regulate car-
diac hypertrophy and that modulation of fibroblast function could be
important for suppression of cardiac remodeling.
6.2.2. Endothelial cells
Studies indicate that endothelial cells communicate with
cardiomyocytes by secreting autocrine and paracrine mediators. Cardiac
endothelial cells secrete vasodilative and vasoconstrictive factors such
as nitric oxide (NO) and endothelin-1 (ET-1). They also secrete physio-
logical active substances such as C-type natriuretic peptide (CNP),
neuregulins (NRGs) and apelin. It is well known that angiogenesis per
se is sufficient to promote cardiac hypertrophy possibly because an in-
crease in the supply of nutrients and oxygen would itself induce hyper-
trophic responses. Accumulating evidence indicates that some of the
humoral mediators secreted by endothelial cells, as described above,
would also modulate this process. NO and CNP are secreted from cardiac
endothelial cells and up-regulate cyclic GMP (cGMP)-cGMP dependent
protein kinase 1 (PKGI) signaling, contributing for the suppression of
cardiac hypertrophy [3,220]. Atrial natriuretic peptide (ANP) and B-
type natriuretic peptide (BNP) are secreted from cardiomyocytes and
also known to activate cGMP-PKGI signaling, thereby inhibit cardiac hy-
pertrophy [129,220]. Neuregulins (NRGs) are part of the epidermal
growth factor family known to be involved in broad biological process-
es. Endothelial cells in adult heart are reported to produce and secrete
NRG-1, which binds to erythroblastic leukemia viral oncogene homolog
(ErbB) receptor. In neonatal rat cardiomyocytes, addition of NRG-1 in-
duced cardiac hypertrophy, and this was suppressed by ErbB inhibition
[221,222]. The role of NRG-1-ErbB signaling in pathological hypertro-
phy is yet to be defined. Apelin is reported to be secreted by endocardial
and endothelial cells and bind to apelin receptor (also known as APJ re-
ceptor) in cardiomyocytes. Injection of apelin did not induce cardiac hy-
pertrophy in rodents and apelin knockout model mice developed
cardiac hypertrophy upon LV pressure-overload. APJ is activated by me-
chanical stretch and mediates hypertrophic response, thereby genetic
depletion of APJ suppressed load induced cardiac hypertrophy in a β-
arrestin dependent manner [223]. ET-1 is a molecule well known to in-
duce cardiac hypertrophy. Addition of ET1 into cardiomyocytes pro-
motes hypertrophy and suppression of ET1 receptor attenuated
cardiac hypertrophy in a rat LV pressure overload model [224,225].
ET1 is secreted from endothelial cells, cardiomyocytes and fibroblasts.
Interestingly, endothelial ET1 depletion led to a worsening of cardiac
function with comparable cardiac hypertrophy upon LV pressure over-
load [226], and further studies are needed to clearly define the cell spe-
cific role of ET1 in heart failure.
6.2.3. Immune cells
In the physiological state, resident cardiac macrophages are pre-
dominantly maintained through self-renewal and to a lesser extent by
recruitment of monocytes. Although pro-inflammatory cytokines such
as TNF-α are known to promote cardiac hypertrophy, the role of inflam-
matory cells in the process of hypertrophy is yet to be defined. Mono-
cyte-derived macrophages increase in response to cardiac injury or
stress. Cardiac hypertrophy or fibrosis does not develop after infusion
of angiotensin II for 2 days, but the macrophage population is already
expanding at this time, suggesting that resident and recruited immune
cells are involved in the early response to stress that precedes cardiac
hypertrophy [227]. In hypertensive Ren-2 rats, depletion of macro-
phages by clodronate resulted in systolic dysfunction and cardiac dilata-
tion, but these changes were not associated with cardiac hypertrophy
[228]. Infusion of angiotensin II ameliorated cardiac fibrosis in MCP-1
KO mice, but cardiac hypertrophy was not improved [229]. Among the
various types of macrophages, it is widely accepted that M1 (classically
activated) macrophages are inflammatory cells that produce pro-in-
flammatory cytokines, while M2 (alternatively activated) macrophages
are anti-inflammatory cells [230,231]. Several subsets of macrophages
have been reported in the mouse heart. The CCR2+ CD11chi subset is
predominantly derived from circulating monocytes and is involved in
cardiac inflammation [227], but other cardiac macrophage subsets
may contribute to maintenance of homeostasis. Since several inflamma-
tory cytokines induce cardiac hypertrophy, analyzing specific
 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
macrophage subsets could help to elucidate their roles in cardiac hyper-
trophy. In addition, the roles of other immune cells, such as T lympho-
cytes, mast cells, and neutrophils, in several models of cardiac
hypertrophy have been reviewed by Ryan et al. [232].
6.3. Endogenous and exogenous factors
6.3.1. Cytokines
There is increasing evidence that inflammation has a central role in
heart failure. In patients with dilated cardiomyopathy, ischemic heart
disease, and myocarditis, cardiac tissue is infiltrated by pro-inflammato-
ry cells such as macrophages and the levels of inflammatory cytokines
are elevated [233]. Studies using several rodent models to investigate
the role of inflammation in heart failure have indicated that an in-
creased inflammatory response generally has an unfavorable impact
on cardiac homeostasis [234–237]. Levels of pro-inflammatory cyto-
kines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and
IL-1β, have been reported to show a correlation with the severity of
heart failure [238]. Cardiomyocyte-specific gain of function for TNF-α
induces cardiac hypertrophy and fibrosis, resulting in dilated cardiomy-
opathy with cardiac dysfunction [239]. Conversely, systemic TNF-α de-
letion ameliorates cardiac hypertrophy and remodeling in a pressure
overload model [240]. Interestingly, TNF-α was shown to have a
cardioprotective role in desmin-deficient mice through ectopic expres-
sion of keratins K8 and K18 [241]. Induction of IL-6 by angiotensin II was
reported to have a causal role in the development of cardiac hypertro-
phy. Overexpression of both IL-6 and the IL-6 receptor in mice induces
concentric cardiac hypertrophy, fibrosis, and diastolic dysfunction
[242,243], while deletion of IL-6 ameliorates angiotensin II-induced car-
diac hypertrophy, inflammation, and fibrosis [244–246]. IL-6 binds to
the IL-6 receptor and activates receptor subunit glycoprotein-130
(gp130). The IL-6/gp130/Janus kinase (JAK)/signal transducer and acti-
vator of transcription (STAT) pathway promotes cardiac hypertrophy
and cardiac dysfunction [247] (Fig. 2). Although the results of these
studies suggested a pathological role of IL-6 in cardiac remodeling, dele-
tion of IL-6 had no effect on cardiac hypertrophy or fibrosis in a pressure
overload model. However, deletion of IL-6st, the gene coding for gp130,
resulted in dilated cardiomyopathy with impaired cardiac function and
increased mortality [248]. Thus, further investigation is required to elu-
cidate the role of IL-6 in cardiac hypertrophy under physiological and
pathological conditions. It was reported that Il1b-deficient mice with
pressure overload show reduced cardiac hypertrophy and improved
cardiac function, indicating that signaling via IL-1β promotes patholog-
ical hypertrophy [249]. Treatment with IL-1β induces cardiac dysfunc-
tion in mice, while a clinical study showed that blockade of IL-1β
signaling increases oxygen consumption and improves exercise toler-
ance in patients with systolic heart failure [250]. These findings suggest
that further clinical trials are warranted to determine whether inhibi-
tion of IL-1β has a favorable effect on heart failure.
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-
κB) is one of the critical regulators of inflammation and is known to in-
crease the production of pro-inflammatory cytokines such as TNF-α. Re-
cently, NF-κB was reported to mediate angiotensin II and endothelin-1
induced cardiomyocyte hypertrophy [251], but data obtained from
transgenic mice are conflicting. In a murine pressure overload model,
deletion of p65 NF-κB in cardiomyocytes reduced cardiac function
along with decreased vascularity and increased fibrosis [252], but an-
other study in a pressure overload model showed that NF-κB/NFAT sig-
naling would promote cardiac hypertrophy and ventricular remodeling
[253].
Interleukin 10 (IL-10) is an anti-inflammatory cytokine, and recently
it was shown to suppress LV-pressure overload induced cardiac hyper-
trophy by the inhibition of NF-κB signaling [254]. Interestingly, in the
LV-pressure overload model, T-cell accumulation was shown to contrib-
ute for an increase in IL-10 expression in cardiac tissue [255].
255
Studies indicate that intercellular communications mediated by pro
or anti-inflammatory cytokines secreted from cardiomyocytes and non-
cardiomyocytes, modulate cardiac hypertrophy and pathologies in
heart failure [232,256,257] (Fig. 3A, B).
As detailed above, various mechanisms contribute to the develop-
ment or suppression of pathological cardiac hypertrophy. Further stud-
ies are needed to elucidate these mechanisms in sufficient detail to
allow development of new therapies for severe heart failure that target
the suppression of cardiac hypertrophy.
7. Angiogenic response in physiological versus pathological cardiac
hypertrophy
Coordination of cardiac growth and angiogenesis appears to be crit-
ically important in separating physiological or adaptive hypertrophy
from pathological cardiac hypertrophy. It has long been observed that
capillary rarefaction occurs in cardiac dysfunction, whereas the number
of capillaries is maintained or increased in hearts with physiological hy-
pertrophy [258–260]. Vascular endothelial growth factor (VEGF) is a
major angiogenic molecule with a pivotal role in vessel formation, de-
velopment, and maintenance of homeostasis in several key organs
[261–263]. Hypertrophic stimuli initially upregulate VEGF expression
in the heart, allowing cardiac growth and angiogenesis to be coordinat-
ed in the adaptive phase of hypertrophy. Shiojima et al. provided the
first evidence that disruption of coordination between cardiac hypertro-
phy and angiogenesis promotes the transition to heart failure [19]. VEGF
deficiency has been reported to occur during pressure overload, which
would lead to a decrease of the capillary density in the heart and pro-
mote the transition from compensatory hypertrophy to cardiac failure
[264]. Hypoxia inducible factor-1α (HIF-1α) and GATA4 are widely
studied regulators of VEGF, with Hif-1α being the major positive regu-
lator of VEGF under hypoxic conditions. During the acute phase of left
ventricular pressure overload, Hif-1α and VEGF maintain pace with
myocardial hypertrophy, while suppression of Hif-1α has a causal role
in the decline of VEGF expression and evidence of cardiac hypoxia dur-
ing the late phase of pressure overload [2]. Recently, the concept that
cardiac hypoxia develops in non-ischemic heart failure is challenged
by a study analyzing dilated cardiomyopathy (DCM) patients. Dass et
al. have performed cardiac magnetic resonance imaging and concluded
that although microvascular dysfunction develops with DCM, cardiac
hypoxia does not develop in this condition. This study suggested the
dissociation between microvascular dysfunction and oxygenation in
DCM patients at least in a rest condition [265]. Further studies are need-
ed to test whether cardiac hypoxia develops in non-ischemic heart fail-
ure patients.
The zinc finger transcription factor GATA4 is abundantly expressed
from the embryonic period to adulthood and regulates cardiac-specific
gene expression. GATA4 promotes angiogenesis by binding to the pro-
moter region of VEGF, thereby regulating transcription of this gene.
Forced expression of GATA4 in adult murine cardiomyocytes enhances
angiogenesis, while myocyte-specific deletion of GATA4 leads to a de-
crease of capillary density [266]. Activation of GATA4 is predominantly
independent of hypoxia and is induced by various molecules involved
in cardiac hypertrophy, such as ERK, p38MAPK, and Akt. Either ERK or
p38MAPK phosphorylates GATA4, leading to up-regulation of its tran-
scriptional activity [267,268]. Interestingly, Hif-1α and GATA4 seem to
regulate the VEGF promoter by acting on distinct regulatory elements
[2,266]. There is evidence to suggest that Akt is one of the critical regu-
lators of angiogenic responses and cell growth. In a hind limb ischemia
model, Akt1 mediates VEGF production and promotes angiogenesis
[269], and Akt also promotes homing of endothelial cells to ischemic re-
gions in vivo [270]. Besides Akt/GATA4 signaling, Akt influences angio-
genesis by promoting the production of nitric oxide (NO) [271–273]. It
has been proposed that an increase of angiogenesis per se is sufficient
to induce cardiac hypertrophy via an NO-dependent or independent
mechanisms. Forced expression of PR39, a peptide regulator of
256 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262

Fig. 3. Modifiers of cardiac hypertrophy. A; Endogenous factors contributing for the induction or suppression of cardiac hypertrophy. Dysregulation in autophagy, DNA and histone
modification, micro RNA and metabolism in cardiomyocytes promote cardiac hypertrophy. TNF-α secreted from cardiomyocytes induces cardiac hypertrophy, in contrast, atrial
natriuretic peptide (ANP), brain natriuretic peptide (BNP) and adrenomedullin inhibit this response in an autocrine manner. B; Exogenous factors contributing for the induction or
suppression of cardiac hypertrophy. Endothelial cells secrete anti-hypertrophic mediators such as nitric oxide (NO), C-type natriuretic peptide (CNP), apelin and adrenomedullin. They
also secrete a pro-hypertrophic factor such as neuregulin-1 (NRG-1). Fibroblasts secrete predominantly pro-hypertrophic molecules such as transforming growth factor β (TGF-β),
insulin like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), connective tissue growth factor (CTGF) and microRNA21 (miR-21). They secrete anti-hypertrophic molecules
like adrenomedullin and interleukin-33 (IL-33). Immune cells also contribute for pro or anti-hypertrophic responses, and these are mediated by TNF-α or interleukin-10 (IL-10)
respectively.

angiogenesis, or placental growth factor induced cardiac hypertrophy in
the absence of hypertrophic stimulations partially via NO mediated sig-
naling [274,275]. In a murine model of cardiac tissue-specific, tetracy-
cline-regulated gain of function for Akt (15-fold increase compared
with normal littermates), short–term induction of Akt (2 weeks) in-
duced physiological hypertrophy together with induction of VEGF, but
forced expression of this gene for 6 weeks led to pathological hypertro-
phy, cardiac dysfunction, and reduced VEGF expression associated with
myocardial capillary rarefaction [19]. These results suggest that the ef-
fect of Akt on the heart depends on the duration and extent of its activa-
tion, and that sustained Akt signaling can be detrimental by promoting
pathological hypertrophy.
Accumulating evidence indicates that capillary rarefaction has a
pathological role in several disorders. During normal pregnancy, physi-
ological cardiac hypertrophy occurs due to expansion of blood volume
and hormonal changes. Peripartum cardiomyopathy (PPCM) is an un-
common complication of pregnancy defined as development of heart
failure with a reduced ejection fraction (b45%) in the last month of
pregnancy or within 5 months of delivery in a patient who has no
other cause of heart failure [276]. The pathogenesis of PPCM is un-
known, but imbalance of cardiac angiogenesis and reduced vascular
density was recently shown to be associated with its development
[277].
Heart failure with reduced ejection fraction (HFrEF) develops due to
the accumulation of myocardial damage and is commonly caused by
myocardial infarction, hypertensive heart disease, or cardiomyopathy.
A marked decrease of myocardial capillary density has been found in pa-
tients with idiopathic dilated cardiomyopathy who develop congestive
heart failure, suggesting that capillary rarefaction has a causative role
in the progression of this disease [278]. Interestingly, mechanical
 I. Shimizu, T. Minamino / Journal of Molecular and Cellular Cardiology 97 (2016) 245–262
unloading by use of a left ventricular assist device (LVAD) is reported to
increase the myocardial microvascular density in patients with HFrEF,
although it accompanied by cardiac fibrosis [279].
Approximately half of all heart failure patients are considered to
have heart failure with a preserved ejection fraction (HFpEF), and this
type of heart failure is predominant among elderly persons [280].
Heart failure is common in the elderly population since its prevalence
shows a dramatic increase with aging (0.3/0.2% among men/women
aged 20–39 years, 1.9/1.4% at 40–59 years, and 14.7/12.8% at
≥80 years) [281]. A recent study showed that cardiac hypertrophy, epi-
cardial coronary artery disease (CAD), coronary microvascular rarefac-
tion, and myocardial fibrosis have a higher prevalence in HFpEF
patients than age-matched controls. Interestingly, the heart weight, car-
diac fibrosis, and microvascular density were similar in HFpEF patients
with or without CAD, while capillary rarefaction was correlated with
myocardial fibrosis, indicating that cardiac endothelial cell remodeling
has a causal role in the onset and progression of HFpEF [3,282]. There
is evidence from several sources that age-related heart failure can de-
velop in the absence of established risk factors such as hypertension,
obesity, diabetes, or atherosclerosis [283–285]. Aging is a normal pro-
cess, but since the incidence and prevalence of heart failure increases
with age, aging seems to predispose for pathological cardiac hypertro-
phy. In a recent study, exposure to the circulation of young mice caused
regression of cardiac hypertrophy in aged mice. This study showed that
circulating growth differentiation factor 11 (GDF11) was responsible for
regression of age-related cardiac hypertrophy, and that the GDF11 level
declines with aging [286]. Another group showed that pathological car-
diac hypertrophy does not develop in mice aged over 24 months old,
and in this setting, GDF11 had no effect on cardiac structure or function.
In this paper, in-vitro studies showed that GDF11 promote cardiomyo-
cyte hypertrophy [287]. GDF11 was recently reported to improve vascu-
lature and enhance neurogenesis in brain [288]. The role of GDF11 in the
maintenance of cardiac homeostasis is yet to be defined, and further
studies are needed to elucidate other potential molecular mechanisms
providing a link between aging and cardiac hypertrophy.
8. Conclusions
Heart failure develops as the result of multiple factors affecting car-
diac function in a complex manner, and this challenging condition does
not respond to simple one-dimensional treatment. Cardiac hypertrophy
is one of the most critical components of cardiac remodeling. Over the
last decade, our understanding of cardiac hypertrophy has made signif-
icant progress and several important signaling molecules and modifiers
involved in hypertrophy have been identified. Continuing investigation
of this field should further improve our understanding of the processes
involved in hypertrophy and may lead to the establishment of next-
generation therapies for heart failure.
Disclosure
I.S. and T.M. disclose no conflict of interests.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research, a
Grant-in-Aid for Scientific Research on Innovative Areas (Stem Cell
Aging and Disease), and a Grant-in-Aid for Exploratory Research from
the Ministry of Education, Culture, Sports, Science and Technology
(MEXT) of Japan and grants from the Ono Medical Research Foundation,
the Japan Diabetes Foundation, the Takeda Science Foundation, the
Takeda Medical Research Foundation, and the Terumo Foundation (to
T.M.) as well as by a Grants-in-Aid for Young Scientists (Start-up)
(JSPS KAKENHI Grant Number 26893080), and grants from the Uehara
Memorial Foundation, Takeda Science Foundation, Kowa Life Science
Foundation, Manpei Suzuki Diabetes Foundation, Kanae Foundation,
257
Japan Heart Foundation Research Grant, The Senri Life Science Founda-
tion, SENSHIN Medical Research Foundation, ONO Medical Research
Foundation, Tsukada Grant for Niigata University Medical Research,
The Nakajima Foundation, SUZUKEN memorial foundation, HOKUTO
Corporation, Inamori Foundation, Mochida Memorial Foundation for
Medical & Pharmaceutical Research, Banyu Foundation Research
Grant, Grant for Basic Science Research Projects from The Sumitomo
Foundation (to I.S.), and by a grant from Bourbon (to T.M. and I.S).
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