Document Detail


Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury.
MedLine Citation:
PMID:  17884027     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: Recent evidence has demonstrated the importance of histone deacetylases (HDAC) in the control of hypertrophic responses in the heart. However, it remains unknown whether inhibition of HDACs plays a role in myocardial ischemia and reperfusion (I/R) injury. We hypothesize that HDAC inhibition triggers preconditioning-like effects against I/R injury. METHODS AND RESULTS: Isolated mouse hearts were perfused with 3 cycles of 5-minute infusion and 5-minute washout of 50 nM of trichostatin A (TSA), a potent inhibitor of HDACs to mimic early pharmacologic preconditioning. This was followed by 30 min of ischemia and 30 min of reperfusion. In addition, mice were treated with saline or TSA (0.1 mg/kg, i.p.) to investigate delayed pharmacologic preconditioning. Twenty-four hours later, the hearts were subjected to I/R. Ventricular function and infarct size were measured, and HDAC 3, 4 and 5 were assessed by Western blot and immunofluorescence. HDAC and p38 mitogen-activated protein kinase activities were determined. TSA produced marked improvements in post-ischemic ventricular function recovery and a reduction in infarct size in both early and delayed preconditioning. Cardioprotection elicited by TSA was abrogated by SB203580, an inhibitor of p38. HDAC 3, 4 and 5 proteins were detected in mouse myocardium. TSA treatments resulted in a significant inhibition of HDAC activity. HDAC inhibition caused a dramatic increase in phosphorylation of p38 and p38 activity. Notably, HDAC inhibition also resulted in remarkable acetylation of p38 at lysine residues. CONCLUSION: These results suggest that inhibition of HDACs triggers pharmacologic preconditioning to protect the ischemic heart, which involves p38 activation.
Authors:
Ting C Zhao; Guangmao Cheng; Ling X Zhang; Yi T Tseng; James F Padbury
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-08-23
Journal Detail:
Title:  Cardiovascular research     Volume:  76     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-11-05     Completed Date:  2009-03-10     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  473-81     Citation Subset:  IM    
Affiliation:
Department of Pediatrics, Women & Infants Hospital, The Warren Alpert Brown Medical School, Brown University, Providence, RI 02905, USA. Tzhao@wihri.org
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MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Histone Deacetylase Inhibitors*
Histone Deacetylases / metabolism
Hydroxamic Acids / pharmacology
Imidazoles / pharmacology
Ischemic Preconditioning, Myocardial*
Male
Mice
Mice, Inbred ICR
Myocardial Infarction / pathology
Myocardial Reperfusion Injury / metabolism*,  prevention & control*
Myocardium / enzymology
Pyridines / pharmacology
Signal Transduction / physiology
Ventricular Function, Left / physiology
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism
Grant Support
ID/Acronym/Agency:
1P20RR01872802/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Imidazoles; 0/Pyridines; 0/SB 203580; 58880-19-6/trichostatin A; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.5.1.98/Histone Deacetylases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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