title: A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair.
abstract: In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF-10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a general inhibitor of NO synthesis. In conclusion, the NO-dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair.
authors: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Istituto di Ricerca e Cura a Carattere Scientifico, 20138 Milan, Italy.
authors: Francesco
authors: F
authors: Spallotta
authors: Chiara
authors: C
authors: Cencioni
authors: Stefania
authors: S
authors: Straino
authors: Simona
authors: S
authors: Nanni
authors: Jessica
authors: J
authors: Rosati
authors: Simona
authors: S
authors: Artuso
authors: Isabella
authors: I
authors: Manni
authors: Claudia
authors: C
authors: Colussi
authors: Giulia
authors: G
authors: Piaggio
authors: Fabio
authors: F
authors: Martelli
authors: Sergio
authors: S
authors: Valente
authors: Antonello
authors: A
authors: Mai
authors: Maurizio C
authors: MC
authors: Capogrossi
authors: Antonella
authors: A
authors: Farsetti
authors: Carlo
authors: C
authors: Gaetano
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D056545:Group III Histone Deacetylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000201:enzymology* / Q000293:injuries*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D020536:Enzyme Activators; D004791:Enzyme Inhibitors; C496463:FGF10 protein, human; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D056545:Group III Histone Deacetylases; C533423:HDAC2 protein, human; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D019331:NG-Nitroarginine Methyl Ester