Cardiac Hypertrophy - NF-AT signaling in Cardiac Hypertrophy

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 Ca(2+)/calcineurin-mediated 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 [1], [2].

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 [3], [4].

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 [5], [6], [7], [8].

Calcineurin A is a calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the nucleus through dephosphorylation and translocation of nuclear transcription factors NFATs [9]. NF-AT3 (NF-ATc4) plays a critical role in calcineurin-mediated cardiac hypertrophic signaling [10].

In the nucleus, NF-AT3 cooperates with other transcription factors, leading to activation of transcription of genes, essential for cardiac development, and, thus, hypertrophy [11], [12], [13].

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 [9]. Glycogen synthase kinase-3 beta (GSK3 beta) is the principal substrate of AKT(PKB) kinase [14]. 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 [15], [16]. GSK3 beta also phosphorylates another transcription factor, GATA-4, and suppresses its nuclear accumulation [17]. GSK3 beta is inactivated by AKT phosphorylation that allows NF-AT3 and GATA-4 to translocate to the nucleus [18], [19].

Induction of gp130 by IL-6, LIF and Cardiotrophyn-1 leads to activation of MAPK pathway [20], [21], [22].

Cardiotrophin-1 and 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 [23], [24], [25].

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 [26], [27], [28].

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) [29], [30], [31], [32]. Protein kinase PKC-mu, a downstream effector of PKC-epsilon, directly phosphorylates HDAC5 and, possibly, HDAC7, and stimulates their export from the nucleus [3], [33], [34].

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 [35], [36].

Transcription factors and co-factors (GATA-4, NKX-2.5, CAMTA2, MEF2, HAND1, 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) [11], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48].

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