Detrimental effect of class-selective histone deacetylase inhibitors during tissue regeneration following hindlimb ischemia

Simona Nanni, Alfredo Pontecorvi, Francesco Spallotta, Silvia Tardivo, Jessica D. Rosati, Stefania Straino, Antonello Mai, Matteo Vecellio, Sergio Valente, Maurizio C. Capogrossi, Antonella Farsetti, Julie Martone, Irene Bozzoni, Carlo Gaetano

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

25 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)22915-22929
Numero di pagine15
RivistaJOURNAL OF BIOLOGICAL CHEMISTRY
Volume288
DOI
Stato di pubblicazionePubblicato - 2013

Keywords

  • Animals
  • Benzamides
  • Dystrophin
  • Epigenetics
  • Hindlimb
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Hydroxamic Acids
  • Ischemia
  • Male
  • Mice
  • Muscle Regeneration
  • Muscle, Skeletal
  • Nitric Oxide
  • Nitric Oxide Synthase Type I
  • Protein Phosphatase 2
  • Protein Phosphatase 2A
  • Pyridines
  • Pyrroles
  • Regeneration
  • Time Factors

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