The NFATc2 transcription factor is required for normal heart function and signaling in adult mice

Abstract

The Ca2+- dependent phosphatase, calcineurin (Cn) and its downstream transcriptional effectors, nuclear factor of activated T-cells (NFAT), are major intracellular modulators of cardiac hypertrophy. In young mice, transcription factor NFATc2 has been identified as the major NFAT isoform responsible for Cn-mediated cardiac hypertrophy. We observed that 7–9 month old NFATc2−/− mice have a higher susceptibility to cardiac dilatation and sudden death, prompting us to monitor changes in heart morphology and growth pathways in this model. Using histology, we show that hearts of adult NFATc2−/− mice display a more dilated left ventricle and thinner interventricular wall. In addition, NFATc2 null hearts have increased GATA-4 expression, higher nuclear transit of GATA-4 and NFATc1, and decreased GSK3-β expression, thus supporting the finding that adult NFATc2−/− mice are more prone to heart failure. Furthermore, angiotensin II-induced cardiac growth reveals that hearts of NFATc2−/− mice hypertrophy to the same extent as wild-type mice, display a thinner myocardial wall and have decreased active AKT and eIF2α expression, suggesting altered translational regulation of myocardial growth. Our collective results propose an uncharacterized role of NFATc2 for normal heart function and growth signaling in adult mice, providing evidence of Cn-signaling being crucial at later stages of life. Supported by CIHR, NSERC and CRC to RNM.