HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment.
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.
Colussi
Claudia
C
Laboratorio di Terapia Genica e Biologia Vascolare, Istituto Cardiologico Monzino, 20138 Milan, Italy.
Mozzetta
Chiara
C
Gurtner
Aymone
A
Illi
Barbara
B
Rosati
Jessica
J
Straino
Stefania
S
Ragone
Gianluca
G
Pescatori
Mario
M
Zaccagnini
Germana
G
Antonini
Annalisa
A
Minetti
Giulia
G
Martelli
Fabio
F
Piaggio
Giulia
G
Gallinari
Paola
P
Steinkuhler
Christian
C
Steinkulher
Christian
C
Clementi
Emilio
E
Dell'Aversana
Carmela
C
Altucci
Lucia
L
Mai
Antonello
A
Capogrossi
Maurizio C
MC
Puri
Pier Lorenzo
PL
Gaetano
Carlo
C
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
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