Abstract
Background
Histone deacetylase inhibitors such as valproic acid (VPA) improve survival in lethal
models of hemorrhagic shock and polytrauma. Although VPA is known to modulate transcription,
its ability to reduce mortality within minutes of administration suggests involvement
of a rapid, posttranslational mechanism. We hypothesized that VPA treatment would
cause proteomic changes within minutes of treatment including quantitative and/or
posttranslational differences in structural and/or effector proteins.
Materials and methods
We used a porcine model of traumatic brain injury (computer-controlled cortical impact,
12 mm depth) and hemorrhagic shock (40% hemorrhage). Animals were kept in shock for
2 h and randomized to two groups (n = 3): normal saline (volume = 3:1 hemorrhage volume) or normal saline + VPA (150 mg/kg,
single dose). Peripheral blood mononuclear cells were collected at baseline, postshock,
and postresuscitation. Intracellular protein profiles were assessed using 1 dimensional
gel electrophoresis, liquid chromatography, mass spectrometry, and analyzed with Ingenuity
Pathway Analysis software.
Results
Animals treated with VPA demonstrated significant proteomic changes. Quantitative
differences were found in over 200 proteins including effector, regulatory, and structural
proteins in critical cell signaling pathways. Posttranslational modification analysis
demonstrated differential VPA-induced acetylation of lysine residues in histone and
nonhistone proteins. Pathway analysis correlated these changes with significant increases
in numerous prosurvival and cytoskeletal intracellular pathways, including Rho GTPase
signaling (P = 1.66E-11), integrin signaling (P = 4.19E-21), and a decrease in Rho guanosine nucleotide dissociation inhibitor signaling
(P = 4.83E-12).
Conclusions
In a porcine model of severe injuries, a single dose of VPA is associated with protective
changes in the proteome that are measurable within minutes of treatment.
Keywords
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Article info
Publication history
Published online: March 29, 2018
Accepted:
February 22,
2018
Received in revised form:
January 10,
2018
Received:
September 19,
2017
Footnotes
Author contributions: M.W., H.B.A helped in conception and design. M.W., V.C.N., I.S.D., P.E.G., M.H.G. helped in data acquisition; M.W., G.A.H., H.R., H.B.A. helped in data interpretation; M.W., V.C.N., I.S.D., G.A.H., H.R. helped in article preparation; all authors helped in critical revisions. H.B.A. provided grant funding.
This study was presented at the Annual Clinical Congress of the American College of Surgeons (San Diego, CA, October 2017).
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
