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Detrimental effect of class-selective histone deacetylase inhibitors during tissue regeneration following hindlimb ischemia.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Aug 09; Vol. 288 (32), pp. 22915-29. Date of Electronic Publication: 2013 Jul 07. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Benzamides pharmacology
Dystrophin metabolism
Hindlimb metabolism
Hindlimb pathology
Histone Deacetylase Inhibitors pharmacology
Histone Deacetylases metabolism
Hydroxamic Acids pharmacology
Male
Mice
Nitric Oxide Synthase Type I metabolism
Protein Phosphatase 2 metabolism
Pyridines pharmacology
Pyrroles pharmacology
Time Factors
Benzamides adverse effects
Hindlimb blood supply
Histone Deacetylase Inhibitors adverse effects
Hydroxamic Acids adverse effects
Ischemia drug therapy
Ischemia metabolism
Ischemia pathology
Muscle, Skeletal blood supply
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
Pyridines adverse effects
Pyrroles adverse effects
Regeneration drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 32
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23836913
- Full Text :
- https://doi.org/10.1074/jbc.M113.484337