NFAT signaling in cardiac hypertrophy
Cardiac hypertrophy is defined as a compensatory mechanism of the heart that helps to
maintain cardiac output during pathological states. Hypertrophy leads to pathologic
cardiac growth, and is associated with increased morbidity and mortality. Transcription
factor NF-AT3 (NFATc4) plays a critical role in
cardiac hypertrophic signaling. NF-AT3 signaling is
essential for normal cardiac valve and may be adapted specifically for transduction
pathologic signals into a hypertrophic response in the heart , .
GPCRs (G-protein coupled receptors) play an important role in the regulation of
cardiac function and adaptation to changes in hemodynamic burden. GPCRs involved in
cardiac hypertrophy include Angiotensin II receptor, type-1
and Beta-1 adrenergic receptor activated by
Angiotensin II and
Noradrenaline, respectively , .
These GPCRs are coupled to three principal classes of heterotrimeric GTP-binding
proteins, G-alphaS, G-alphaI and G-alphaQ/11 which transduce signals towards
intracellular effectors such as enzymes and ion channels. G-proteins consist of the
subunits G-alpha (G-protein alpha-s, G-protein
alpha-i family and G-protein alpha-q/11) and
G-beta/gamma (G-proteins beta/gamma), which upon receptor
activation dissociate and independently activate signaling pathways, including activation
of kinases (such as c-Src,
PKC-epsilon and PKC-alpha),
MAPK cascade, and increase in intracellular
Ca(2+) level , , , .
Calcineurin A is a
serine-threonine phosphatase that transmits signals to the nucleus through
dephosphorylation and translocation of nuclear transcription factors NFATs . NF-AT3 (NF-ATc4) plays a critical role in
calcineurin-mediated cardiac hypertrophic signaling .
In the nucleus, NF-AT3 cooperates with other
transcription factors, leading to activation of transcription of genes, essential for
cardiac development, and, thus, hypertrophy , , .
Other receptors associated with the induction of cardiac hypertrophy through the
NF-AT3 pathway include IGF-1 receptor,
activated by IGF-1 (Insulin Like Growth
Factor-1) and gp130, which functions as a part of the
cytokine receptor complex and is shared by many cytokines, including interleukin 6
(IL-6), leukemia inhibitory factor
(LIF) and Cardiotrophin-1.
IGF-1 stimulates the phosphoinositide 3-kinase
(PI3K)/AKT pathway, which has
been shown to promote hypertrophy of cardiomyocytes . Glycogen synthase
kinase-3 beta (GSK3 beta) is the principal substrate of
AKT(PKB) kinase . The activated
GSK3 beta suppresses cardiac hypertrophy, since
GSK3 beta phosphorylates NFAT proteins and, thus,
antagonizes action of Calcineurin A by stimulating
NF-AT3 nuclear export , .
GSK3 beta also phosphorylates another transcription factor,
GATA-4, and suppresses its nuclear accumulation . GSK3 beta is inactivated by
AKT phosphorylation that allows
NF-AT3 and GATA-4 to
translocate to the nucleus , .
Induction of gp130 by IL-6,
LIF and Cardiotrophyn-1 leads
to activation of MAPK pathway , , .
LIF-induced activation of gp130
transduces hypertrophic signal through interaction of scaffolding/docking protein
GAB1 with tyrosine phosphatase
SHP-2 in cardiomyocytes.
GAB1/SHP-2 signaling regulates
activation of MEK5/ERK5 MAP
kinases, leading to gp130-dependent elongation of
cardiomyocytes , , .
ERK5 phosphorylates and activates transcription factors
of the myocyte enhancer factor 2 (MEF2) family (MEF2A,
MEF2C, MEF2D) that nave been
implicated as a signal-responsive mediators of the cardiac transcriptional program , , .
Class II histone deacetylases (HDAC4,
HDAC5, HDAC7 and
HDAC9) have been shown to interact with
MEF2s and play an important role in the repression of
cardiac hypertrophy. Class II HDAC activity is inhibited by
calcineurin and through phosphorylation by
Ca2+/calmodulin-dependent kinase (CaMKIV) , , , . Protein kinase
PKC-mu, a downstream effector of
PKC-epsilon, directly phosphorylates
HDAC5 and, possibly, HDAC7, and
stimulates their export from the nucleus , , .
The calmodulin binding transcription activator 2 (CAMTA2)
is shown to be an indispensable transcription coactivator for cardiac hypertrophy.
CAMTA2 is activated by the dissociation of
HDAC5 and promotes transcription of genes through its
interaction with Nkx2-5 , .
Transcription factors and co-factors (GATA-4,
HAND2, CBP and
p300) cooperate with NF-AT3 to
express genes, involved in cardiac hypertrophy, including alpha- and beta-myosin
(alpha-MHC and beta-MHC);
Troponin I, cardiac; Troponin T,
cardiac; Sodium/calcium exchanger NCX1;
Endothelin-1; Actin, alpha cardiac
(ACTC); Adenylosuccinate synthetase
(ADSSL1); and Atrial natriuretic factor
(ANP) , , , , , , , , , , , , .
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