NFATandHypertrophyoftheheart(Transcriptioninthebrokenheart)

Hypertrophy associated with both hypertension and obstruction to ventricular outflow leads to pathologic cardiac growth and it is associated with increase morbidity and mortality. Symptomatic ventricular disease takes a growing toll on the health of nations. As other cardiovascular diseases such as stroke and myocardial infraction are in decline as causes of mortality, the heart failure problem becomes increasingly urgent. Congenital heart defects occur in 1% of live births and fetal heart malformations are implicated in many pregnancies that end in still-birth or spontaneous abortion. The current paradigm suggests that the heart adapts to excess of hemodynamic loading by compensatory hypertrophy, which under condition of persistent stress, over time evolves into dysfunction and myocardial failure. There is considerable evidence that direct effects of increased mechanical stress are sensed within the ventricular wall and that signals critical for the generation of growth responses. Despite compelling statistics we still do not understand biochemically why heart defects are so prevalent. A single transcriptional regulator initially associated with the activation of the T-cells (NFATc4) has been shown to link genetic and environmental causes of one class of congenital heart disorders – birth defects involving valve and septum formation. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc4. Activated CaMK stimulates calcineurin, which than acts through NF-ATc4 in association with GATA4, to induce hypertrophy. A model for the proposed role of calreticulin in the regulation of cardiac development requires a myogenic signal from extracellular space to activate the production of IP3 that results in the release of Ca2+ from ER under the regulation of calreticulin (CRT). Increased intracellular Ca2+ binds to calmodulin (CaM) and activates calcineurin (CaN). CaN dephosphorylates NF-ATc4 that translocates to the nucleus. In the nucleus NF-AT forms complexes with the GATA-4 and other transcription factors leading to activation of transcription of genes (ANF, a-actin, b-mysin, TNFa, ET-1, Adss1 etc) essential for cardiac development. For a comprehensive list of myocyte genes regulated at transcriptional level see Molecular and Cellular Biology of Cardiac Hypertrophy and Failure by Hunter et al., in Molecular Basis of Cardiovascular Disease ed by Chien KR, pp 211-250)

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