Background
DNA transcription is regulated, in part, by acetylation of nuclear histones that are
controlled by 2 groups of enzymes: histone deacetylases (HDAC) and histone acetyl
transferases (HAT). Whether an imbalance in HDAC/HAT system plays a role in hemorrhage/resuscitation
is unknown. The goals of this study were to determine whether hemorrhage results in
deacetylation of cardiac histones and whether this can be corrected through the application
of different resuscitation strategies or specific HDAC inhibitors.
Methods
In the first experiment, rats (n = 6 per group) were subjected to volume-controlled
hemorrhage and resuscitated with racemic lactated Ringer’s solution, L-lactated Ringer’s
solution, 7.5% hypertonic saline solution, ketone Ringer’s solution, and pyruvate
Ringer’s solution. Control groups included no hemorrhage (sham) and hemorrhage with
no resuscitation. In the second experiment (n = 5 per group), 3 HDAC inhibitors (valproic
acid, trichostatin A, and suberoylanilide hydroxamic acid) were added to saline solution
resuscitation. Heart tissue was collected at the end of resuscitation. Isolated subcellular
protein fractions were used in Western blotting to analyze the patterns of total protein
acetylation and histone acetylation specifically. HDAC and HAT activity was measured
in tissue extracts.
Results
Hemorrhage led to partial histone deacetylation. Resuscitation resulted in protein
hyperacetylation in nuclear fractions only. A detailed analysis of histones (on 10
acetylation sites) revealed that ketone Ringer’s solution hyperacetylated histones
H2B, H3, and H4. The addition of suberoylanilide hydroxamic acid hyperacetylated histones
more effectively than other resuscitation strategies, presumably by direct inhibition
of HDAC activity.
Conclusion
Hemorrhage/resuscitation is associated with HDAC/HAT activity misbalance, and the
acetylation status of cardiac histones is influenced by the choice of resuscitation
strategy. Shock-induced changes can be reversed through the infusion of pharmacologic
HDAC inhibitor, even when it is administered after the insult for a limited period
of time.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to SurgeryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Pattern of organ failure following severe trauma.World J Surg. 1996; 20: 422-429
- Histone modifications in transcriptional regulation.Curr Opin Genet Dev. 2002; 12: 142-148
- Histone deacetylase inhibitors.Expert Opin Investig Drugs. 2002; 11: 1695-1713
- Histone deacetylases and cancer.Natl Rev Cancer. 2001; 1: 194-202
- Emerging roles for chromatin remodeling in cancer biology.Trends Cell Biol. 2001; 11: S15-S21
- Histone deacetylases as a therapeutic target.Trends Endocrinol Metab. 2001; 12: 294-300
- Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males.Am J Physiol. 1997; 273: H2919-H2925
- Heart function after severe hemorrhagic shock.Shock. 1999; 12: 454-461
- Wassarman P.M. Wolfe A.P. Chromatin: methods in enzymology. vol 304. Academic Press, San Diego1999
- An increasingly complex code.J Clin Invest. 2002; 110: 577-582
- The language of covalent histone modifications.Nature. 2000; 403: 41-45
- cDNA array analysis of gene expression following hemorrhagic shock and resuscitation in rats.Resuscitation. 2002; 54: 195-206
- Effect of myocardial ischemia on uridine incorporation and histone acetylation.Can J Physiol Pharmacol. 1982; 60: 313-318
- Histone acetylation in chromatin structure and transcription.Nature. 1999; 389: 349-352
- Redox modulation of chromatin remodeling.Biochem Pharmacol. 2004; 68: 1255-1267
- Transcription.Curr Biol. 1998; 8: R422-R424
- Regulation of gene expression by transcription factor acetylation.Cell Mol Life Sci. 2000; 57: 1184-1192
- Histone acetylation.Trends Biochem Sci. 1997; 22: 128-132
- Histone deacetylases (HDACs).Biochem J. 2003; 370: 737-749
- Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway.Proc Natl Acad Sci. 2003; 100: 4281-4286
- Histone deacetylase inhibitors arrest polyglutamine-dependent neurogeneration in Drosophila.Nature. 2001; 413: 739-743
- Regulation of lifespan by histone deacetylase.Ageing Res Rev. 2002; 1: 313-326
- The antitumor histone deacetylase inhibitor SAHA exhibits antiinflammatory properties via suppression of cytokines.Proc Natl Acad Sci. 2002; 99: 2995-3000
- The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses.BMC Cancer. 2003; 3: 30-48
- A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis.Mol Ther. 2003; 8: 707-717
- Ketone and pyruvate Ringer’s solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation.Surgery. 2003; 134: 267-275
- Searching for the optimal resuscitation method.J Trauma. 2003; 54: S52-S62
Article info
Publication history
Accepted:
August 18,
2005
Bethesda, Md, Washington, DC, and Boston, MassFootnotes
Supported in part by Office of Naval Research grants: MDA 905-99-1-0022 (E.K.) and MDA905-03-1-004 (H.B.A.).
Identification
Copyright
© 2006 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
