title: Detrimental effect of class-selective histone deacetylase inhibitors during tissue regeneration following hindlimb ischemia.
abstract: Histone deacetylase inhibitors (DIs) are promising drugs for the treatment of several pathologies including ischemic and failing heart where they demonstrated efficacy. However, adverse side effects and cardiotoxicity have also been reported. Remarkably, no information is available about the effect of DIs during tissue regeneration following acute peripheral ischemia. In this study, mice made ischemic by femoral artery excision were injected with the DIs MS275 and MC1568, selective for class I and IIa histone deacetylases (HDACs), respectively. In untreated mice, soon after damage, class IIa HDAC phosphorylation and nuclear export occurred, paralleled by dystrophin and neuronal nitric-oxide synthase (nNOS) down-regulation and decreased protein phosphatase 2A activity. Between 14 and 21 days after ischemia, dystrophin and nNOS levels recovered, and class IIa HDACs relocalized to the nucleus. In this condition, the MC1568 compound increased the number of newly formed muscle fibers but delayed their terminal differentiation, whereas MS275 abolished the early onset of the regeneration process determining atrophy and fibrosis. The selective DIs had differential effects on the vascular compartment: MC1568 increased arteriogenesis whereas MS275 inhibited it. Capillarogenesis did not change. Chromatin immunoprecipitations revealed that class IIa HDAC complexes bind promoters of proliferation-associated genes and of class I HDAC1 and 2, highlighting a hierarchical control between class II and I HDACs during tissue regeneration. Our findings indicate that class-selective DIs interfere with normal mouse ischemic hindlimb regeneration and suggest that their use could be limited by alteration of the regeneration process in peripheral ischemic tissues.
authors.affiliation: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, 20138 Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Spallotta
authors.forename: Silvia
authors.initials: S
authors.lastname: Tardivo
authors.forename: Simona
authors.initials: S
authors.lastname: Nanni
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Rosati
authors.forename: Stefania
authors.initials: S
authors.lastname: Straino
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Matteo
authors.initials: M
authors.lastname: Vecellio
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.forename: Julie
authors.initials: J
authors.lastname: Martone
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.forename: Claudia
authors.initials: C
authors.lastname: Colussi
mesh_terms: D000818:Animals; D001549:Benzamides / Q000009:adverse effects* / Q000494:pharmacology; D016189:Dystrophin / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000009:adverse effects* / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects* / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects*; D013997:Time Factors
chemical_list: D001549:Benzamides; D016189:Dystrophin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C577554:MC1568; D011725:Pyridines; D011758:Pyrroles; C118739:entinostat; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D054648:Protein Phosphatase 2; D006655:Histone Deacetylases
keywords: Epigenetics; Histone Deacetylase Inhibitors; Ischemia; Muscle Regeneration; Nitric Oxide; Protein Phosphatase 2A