Role of NFAT in Cardiac Hypertrophy


Pathway Description

Cardiac failure is often associated with prolonged and maladaptive cardiac hypertrophy, defined as a compensatory mechanism of the heart that helps to maintain cardiac output during pathological states with sustained increases in hemodynamic load. As cardiomyocytes lose the ability to divide soon after birth, cardiac hypertrophy offers an important adaptive response in vivo which allows the organism to maintain or increase its cardiac output. The adult myocardium responds to a wide array of intrinsic and extrinsic stimuli including hypertension, myocardial infarction, cardiac arrhythmias, valvular disease and endocrine disorders by hypertrophic growth. Although initially beneficial, prolonged hypertrophy is correlated with poor clinical prognosis resulting in dilated cardiomyopathy, heart failure, and sudden death.The hypertrophic response is orchestrated by growth factors and cytokines acting through several interdependent signaling cascades whose molecules include G-proteins, GTPases such as Ras, RhoA and Rac, and kinases such as ERK/MAPK and PKC. Recent studies have also recognized the importance of Ca2+ sensitive signaling molecules, including calcineurin and CAMK in hypertrophic pathways. In all of these pathways, nuclear factor Of activated T cells (NFAT) plays a central role in the development of cardiac hypertrophy. NFAT is a family of transcription factors composed of four structurally related members: NFATc, NFATp, NFAT3 and NFAT4 that are expressed in the cytoplasm of resting cells, as well as NFAT5 which is found exclusively in the nucleus. Of these, NFAT3/NFATC4 is expressed in the adult heart and mediates the signals of cardiac hypertrophy. The initial phase in the development of myocardial hypertrophy involves factors such as endothelin-1, angiotensin-II, and adrenergic agonists at the cell membrane, the receptors of which are coupled to G-proteins of the Gαq, Gαs and Gαi families. Other receptors associated with the induction of hypertrophy through the NFATC4 pathway include IGF1 and GP130. G-proteins activate downstream molecules such as PKC, PKA and Ras. Activation of PKC leads to changes in Ca2+ handling through phosphorylation of channels and pumps and increases in NHE1. The activation of PKA eventually leads to increased Ca2+ levels that activate the protein phosphatase calcineurin. Calcineurin activation leads to the dephosphorylation of NFATc4, allowing its nuclear localization where it cooperates with other transcription factors to participate in the formation transcriptional regulatory complexes. Other signaling pathways including the Ras/Raf/ERK, MKK(3/6)/JNK and MKK(4/7)/p38 MAPK phosphorylate NFATC4. Phosphorylation of NFATC4 usually opposes nuclear localization of NFATC4 either by promoting nuclear export or by impeding nuclear import.

NFATC4 remains in a phosphorylated condition under basal, unstimulated conditions. Dephosphorylation mediated by calcineurin promotes nuclear translocation and subsequent transcriptional activation of NFATC4, whereas re-phosphorylation terminates the activation of NFATC4. p38 MAPK, JNK and additional kinases such as GSK3β and CSNK1-α mediate re-phosphorylation of NFATc4 and thus act as negative regulators of cardiac hypertrophy. NFAT proteins cooperate with other transcription factors such as GATA4, CBP, p300 and MEF2 leading to transcription of genes such as ANF, α-actin, β-myosin and TNF-α, which are essential for cardiac development and hypertrophy.