Valproic acid prevents hemorrhage-associated lethality and affects the acetylation pattern of cardiac histones

Earl Gonzales, Huazhen Chen, Richard Munuve, Tina Mehrani, Joy Britten-Webb, Amal Nadel, Hasan B. Alam, David Wherry, David Burris, Elena Koustova*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Pharmacological inhibitors of histone deacetylases (HDAC) demonstrate cytoprotective effects both in vitro and in vivo. In this study, we investigated whether valproic acid (VPA), a known mood stabilizer and anticonvulsant with HDAC-inhibiting activity, improves survival following otherwise lethal hemorrhage in rats. We found that preinsult injection of VPA (300 mg/kg, twice) prolonged the survival of severely hypotensive animals up to 5 times. VPA treatment increased the acetylation of nonhistone and histone proteins in the rat heart. The pattern of modifications of individual histones revealed hyperacetylation of histones H2A, H3, and H4, indicating the presence of active genes. Expression of HSP70 and superoxide dismutase, implicated in the modulation of vitality, was increased by VPA. Our results reveal that VPA offers considerable protection in the hemorrhagic shock model and suggest a role for HDAC inhibition in mediating VPA actions.

Original languageEnglish (US)
Pages (from-to)395-401
Number of pages7
JournalShock
Volume25
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Keywords

  • Gene expression
  • Hemorrhagic shock
  • Histone code
  • Histone deacetylase
  • Hyperacetylation
  • Survival
  • Valproic acid

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

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