Simona Nanni1, Agnese Re2, Cristian Ripoli3, Aoife Gowran4, Patrizia Nigro4, Domenico D'Amario5, Antonio Amodeo6, Filippo Crea5, Claudio Grassi3,7, Alfredo Pontecorvi1, Antonella Farsetti2,8, Claudia Colussi2. 1. Institute of Medical Pathology, Università Cattolica, Rome 00168, Italy. 2. Institute of Cell Biology and Neurobiology, National Research Council, Rome 00143, Italy. 3. Institute of Human Physiology, Medical School, Università Cattolica, Rome 00168, Italy. 4. Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino, Milan 20138, Italy. 5. Department of Cardiovascular Medicine, Università Cattolica, Rome 00168, Italy. 6. Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy. 7. San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, 00163 Rome, Italy. 8. Goethe University, Internal Medicine Clinic III, Frankfurt am Main 60590, Germany.
Abstract
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Christina Schoenherr; Adam Byron; Billie Griffith; Alexander Loftus; Jimi C Wills; Alison F Munro; Alex von Kriegsheim; Margaret C Frame Journal: J Biol Chem Date: 2020-07-02 Impact factor: 5.157
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