title: HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment.
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.
authors.affiliation: Laboratorio di Terapia Genica e Biologia Vascolare, Istituto Cardiologico Monzino, 20138 Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Colussi
authors.forename: Chiara
authors.initials: C
authors.lastname: Mozzetta
authors.forename: Aymone
authors.initials: A
authors.lastname: Gurtner
authors.forename: Barbara
authors.initials: B
authors.lastname: Illi
authors.forename: Jessica
authors.initials: J
authors.lastname: Rosati
authors.forename: Stefania
authors.initials: S
authors.lastname: Straino
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ragone
authors.forename: Mario
authors.initials: M
authors.lastname: Pescatori
authors.forename: Germana
authors.initials: G
authors.lastname: Zaccagnini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Antonini
authors.forename: Giulia
authors.initials: G
authors.lastname: Minetti
authors.forename: Fabio
authors.initials: F
authors.lastname: Martelli
authors.forename: Giulia
authors.initials: G
authors.lastname: Piaggio
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkuhler
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkulher
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.forename: Carmela
authors.initials: C
authors.lastname: Dell'Aversana
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000166:cytology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000201:enzymology
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C118739:entinostat; D009569:Nitric Oxide; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D009584:Nitrogen