HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment

Claudia Colussi, Chiara Mozzetta, Aymone Gurtner, Barbara Illi, Jessica Rosati, Stefania Straino, Gianluca Ragone, Mario Pescatori, Germana Zaccagnini, Annalisa Antonini, Giulia Minetti, Fabio Martelli, Giulia Piaggio, Paola Gallinari, Christian Steinkulher, Emilio Clementi, Carmela Dell'Aversana, Lucia Altucci, Antonello Mai, Maurizio C. CapogrossiPier Lorenzo Puri, Carlo Gaetano

Research output: Contribution to journalArticle

Abstract

The overlapping histological and biochemical features underlying the beneficial effect of deacetylase inhibitors and NO donors in dystrophic muscles suggest an unanticipated molecular link among dystrophin, NO signaling, and the histone deacetylases (HDACs). Higher global deacetylase activity and selective increased expression of the class I histone deacetylase HDAC2 were detected in muscles of dystrophin-deficient MDX mice. In vitro and in vivo siRNA-mediated down-regulation of HDAC2 in dystrophic muscles was sufficient to replicate the morphological and functional benefits observed with deacetylase inhibitors and NO donors. We found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation. These data reveal a special contribution of HDAC2 in the pathogenesis of Duchenne muscular dystrophy and indicate that HDAC2 inhibition by NO-dependent S-nitrosylation is important for the therapeutic response to NO donors in MDX mice. They also define a common target for independent pharmacological interventions in the treatment of Duchenne muscular dystrophy.

Original languageEnglish
Pages (from-to)19183-19187
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number49
DOIs
Publication statusPublished - Dec 9 2008

Keywords

  • Epigenetic
  • Skeletal muscle

ASJC Scopus subject areas

  • General

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    Colussi, C., Mozzetta, C., Gurtner, A., Illi, B., Rosati, J., Straino, S., Ragone, G., Pescatori, M., Zaccagnini, G., Antonini, A., Minetti, G., Martelli, F., Piaggio, G., Gallinari, P., Steinkulher, C., Clementi, E., Dell'Aversana, C., Altucci, L., Mai, A., ... Gaetano, C. (2008). HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment. Proceedings of the National Academy of Sciences of the United States of America, 105(49), 19183-19187. https://doi.org/10.1073/pnas.0805514105