AIMS: Beyond the control of nuclear-cytoplasmic trafficking nucleoporins 
regulate gene expression and are involved in cardiac diseases. Notably, a number 
of cardiovascular disorders have been linked to alterations in epigenetic 
mechanisms. Here we aimed to determine the contribution of Nup153 to the 
epigenetic alterations occurring in cardiomyopathy of dystrophin-deficient mdx 
mice (C57BL/10ScSn-Dmd mdx /J).
METHODS AND RESULTS: Nup153 was lysine-acetylated and its expression was 
significantly increased at protein level in mdx hearts compared with controls. 
Accordingly, lysine acetyl transferase (KAT) activity associated with Nup153 was 
higher in mdx hearts paralleling increased binding with the lysine acetylases 
P300/CBP-associated factor (PCAF) and p300. Interestingly, Nup153 silencing in 
mdx organotypic heart tissue slices caused a reduction in PCAF- and 
p300-specific activities. Remarkably, the level of nitric oxide (NO), which is 
reduced in mdx mice, was important for KAT-dependent regulation of Nup153. In 
fact, treatment of mdx heart tissue with an NO donor or the KAT inhibitor 
anacardic acid normalized Nup153 protein expression. Nup153 was recruited to 
chromatin and regulated the transcription of genes involved in cardiac 
remodelling, including the actin-binding protein nexilin. Accordingly, nexilin 
protein expression was abrogated by Nup153 silencing in mdx organotypic 
cultures. Electrophysiological and molecular experiments revealed that Nup153 
overexpression in normal cardiomyocytes increases Ca v 1.2 calcium channel 
expression and function. Alterations in Nup153 protein expression and 
intracellular localization were also found in dystrophic cardiomyocytes derived 
from patient-specific induced pluripotent stem cells. Importantly, Nup153 
up-regulation and increased acetylation were also found in the heart of Duchenne 
muscular dystrophy patients.
CONCLUSIONS: Our data indicate that Nup153 is an epigenetic regulator which, 
upon altered NO signalling, mediates the activation of genes potentially 
associated with early dystrophic cardiac remodelling.