Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model

Panpan Chang, Michael Weykamp, Isabel S. Dennahy, Aaron M. Williams, Umar F. Bhatti, Baoling Liu, Vahagn C. Nikolian, Yongqing Li, Hasan B. Alam

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

BACKGROUND Hemorrhage is a leading preventable cause of death. Nonselective histone deacetylase inhibitors (HDACIs), such as valproic acid (VPA), have been shown to improve outcomes in hemorrhagic shock (HS). The HDACs can be divided into four functional classes (I, IIa/IIb, III, and IV). Classes I, IIa/IIb, and III have previously been implicated in the pathophysiology of HS. This study aimed to determine which HDAC class, or classes, are responsible for the survival benefit observed with nonselective HDACIs. METHODS Survival study: Sprague-Dawley rats were subjected to lethal HS (50% hemorrhage) and randomized to the following groups (n = 8): (1) no treatment, (2) normal saline vehicle, (3) cyclodextrin vehicle, (4) MS275 (class I HDACI), (5) VPA (class I/IIa HDACI), (6) MC1568 (class IIa HDACI), (7) ACY1083 (class IIb HDACI), and (8) EX527 (class III HDACI). Survival was monitored for 24 hours. Mechanistic study: Sprague-Dawley rats were subjected to sublethal HS (40% hemorrhage) and randomized to the same groups (n = 3), excluding EX527, based on results of the survival study. Tissues were harvested at 3 hours posttreatment, and expression of phosphorylated-AKT, β-catenin, acetylated histones H3 and H4, and acetylated α-tubulin were analyzed in myocardial tissue. RESULTS Survival rate was 12.5% in the untreated group, and did not improve with vehicle or MS275 treatment. EX527 improved survival to 50%, although this did not achieve statistical significance (p = 0.082). However, treatment with VPA, MC1568, and ACY1083 improved survival rates to 87.5%, 75%, and 75%, respectively (p < 0.05). The VPA-induced acetylation of both histones H3 and H4, while MC1568 and ACY1083 increased acetylation of histone H4. ACY1083 also induced acetylation of α-tubulin. All treatment groups, except MS275, increased phosphorylated-AKT, and β-catenin. CONCLUSION Inhibition of HDAC classes IIa or IIb, but not class I, activates prosurvival pathways, which may be responsible for the improved outcomes in rodent models of HS.

Original languageEnglish (US)
Pages (from-to)795-801
Number of pages7
JournalJournal of Trauma and Acute Care Surgery
Volume84
Issue number5
DOIs
StatePublished - May 1 2018
Externally publishedYes

Keywords

  • Histone deacetylase inhibitors
  • hemorrhagic shock
  • isoform-selective
  • prosurvival pathways
  • valproic acid

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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