Urocortin II (UcnII) a cardioactive peptide with beneficial effects in normal and failing hearts, is also arrhythmogenic and pro-hypertrophic. We demonstrated that cardiac effects are mediated by a PI3K/Akt/eNOS/NO signaling pathways. Nuclear factor of activated T-cells (NFAT) transcription factors play a key role in the regulation of gene expression in cardiac development, maintenance of an adult differentiated cardiac phenotype and remodeling processes in cardiac hypertrophy and heart failure (HF). We tested the hypothesis that UcnII differentially regulates NFAT activity in cardiac myocytes from both normal and failing hearts through the PI3K/Akt/eNOS/NO pathway. Isoforms NFATc1 and NFATc3 revealed different basal subcellular distribution in normal and HF rabbit ventricular myocytes with a nuclear NFATc1 and a cytosolic localization of NFATc3. However, in HF, the nuclear localization of NFATc1 was less pronounced whereas the nuclear occupancy of NFATc3 was increased. In normal myocytes UcnII induced nuclear export of NFATc1 and attenuated NFAT-dependent transcriptional activity, but did not affect the distribution of NFATc3. In HF UcnII facilitated nuclear export of both isoforms and reduced transcriptional activity. NFAT regulation was mediated by a PI3K/Akt/eNOS/NO signaling cascade that converged on the activation of several kinases, including GSK3β, JNK, p38 and PKG, resulting in phosphorylation, deactivation and nuclear export of NFAT. In conclusion, while NFATc1 and NFATc3 reveal distinct subcellular distribution patterns, both are regulated by the UcnII-PI3K/Akt/eNOS/NO pathway, that converges on the activation of NFAT kinases and NFAT inactivation. The data reconcile cardioprotective and pro-hypertrophic UcnII effects mediated by different NFAT isoforms.
- cardiac myocytes
- nuclear factor of activated T-cells (NFAT)
- heart failure
- Copyright © 2013, American Journal of Physiology - Heart and Circulatory Physiology