Alterations in the human proteome following administration of valproic acid

Patrick E. Georgoff, Ihab Halaweish, Vahagn C. Nikolian, Gerald A. Higgins, Tess Bonham, Celia Tafatia, Henriette Remmer, Rajasree Menon, Baoling Liu, Yongqing Li, Hasan B. Alam

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

BACKGROUND High doses of the histone deacetylase inhibitor valproic acid (VPA, 150-400 mg/kg) improve outcomes in animal models of lethal insults. We are conducting a US Food and Drug Administration-approved Phase I, double-blind, placebo-controlled trial to evaluate the safety and tolerability of ascending doses of VPA in human volunteers. We hypothesized that VPA would induce significant changes in the proteome of healthy humans when given at doses lower than those used in prior animal studies. METHODS Peripheral blood mononuclear cells were obtained from three healthy subjects randomized to receive VPA (120 mg/kg over 1 hour) at baseline and at 4 and 8 hours following infusion. Detailed proteomic analysis was performed using 1D gel electrophoresis, liquid chromatography, and mass spectrometry. Proteins with differential expression were chosen for functional annotation and pathway analysis using Ingenuity Pathway Analysis (Qiagen GmbH, Hilden, Germany) and Panther Gene Ontology. RESULTS A total of 3,074 unique proteins were identified. The average number of proteins identified per sample was 1,716 ± 459. There were a total of 140 unique differentially expressed proteins (p < 0.05). There was a minor and inconsistent increase in histone and nonhistone protein acetylation. Functional annotation showed significant enrichment of apoptosis (p = 3.5E-43), cell death (p = 9.9E-72), proliferation of cells (p = 1.6E-40), dementia (p = 9.6E-40), amyloidosis (p = 6.3E-38), fatty acid metabolism (p = 4.6E-76), quantity of steroid (p = 4.2E-75), and cell movement (p = 1.9E-64). CONCLUSIONS Valproic acid induces significant changes to the proteome of healthy humans when given at a dose of 120 mg/kg. It alters the expression of key proteins and pathways, including those related to cell survival, without significant modification of protein acetylation. In the next part of the ongoing Phase I trial, we will study the effects of VPA on trauma patients in hemorrhagic shock.

Original languageEnglish (US)
Pages (from-to)1020-1026
Number of pages7
JournalJournal of Trauma and Acute Care Surgery
Volume81
Issue number6
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Keywords

  • Cell regulation
  • histone deacetylase inhibitors
  • pathways
  • proteomics
  • valproic acid

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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