Document Detail


Inhibition of histone deacetylases preserves myocardial performance and prevents cardiac remodeling through stimulation of endogenous angiomyogenesis.
MedLine Citation:
PMID:  22271820     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously shown that the inhibition of histone deacetylases (HDACs) protects the heart against acute myocardial ischemia and reperfusion injury. We also demonstrated that HDAC inhibition stimulates myogenesis and angiogenesis in a cultured embryonic stem cell model. We investigate whether in vivo inhibition of HDAC preserves cardiac performance and prevents cardiac remodeling in mouse myocardial infarction (MI) through the stimulation of endogenous regeneration. MI was created by ligation of the left descending artery. Animals were divided into three groups: 1) sham group, animals that underwent thoracotomy without MI; 2) MI, animals that underwent MI; and 3) MI + trichostatin A (TSA), MI animals that received a daily intraperitoneal injection of TSA. In addition, infarcted mice received a daily intraperitoneal injection of TSA (0.1 mg/kg), a selective HDAC inhibitor. 5-Bromo-2-deoxyuridine (50 mg/kg) was delivered every other day to pulse-chase label in vivo endogenous cardiac replication. Eight weeks later, the MI hearts showed a reduction in ventricular contractility. HDAC inhibition increased the improvement of myocardial functional recovery after MI, which was associated with the prevention of myocardial remodeling and reduction of myocardial and serum tumor necrosis factor α. HDAC inhibition enhanced the formation of new myocytes and microvessels, which was consistent with the robust increase in proliferation and cytokinesis in the MI hearts. An increase in angiogenic response was demonstrated in MI hearts receiving TSA treatment. It is noteworthy that TSA treatment significantly inhibited HDAC activity and increased phosphorylation of Akt-1, but decreased active caspase 3. Taken together, our results indicate that HDAC inhibition preserves cardiac performance and mitigates myocardial remodeling through stimulating cardiac endogenous regeneration.
Authors:
Ling Zhang; Xin Qin; Yu Zhao; Loren Fast; Shougang Zhuang; Paul Liu; Guangmao Cheng; Ting C Zhao
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-01-23
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  341     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-15     Completed Date:  2012-05-04     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  285-93     Citation Subset:  IM    
Affiliation:
Cardiovascular Laboratories, Department of Surgery, Boston University Medical School, Roger William Medical Center, 50 Maude Street, Providence, RI 02908, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Histone Deacetylase Inhibitors / pharmacology*,  therapeutic use
Histone Deacetylases / metabolism*
Hydroxamic Acids / pharmacology,  therapeutic use
Male
Mice
Mice, Inbred ICR
Muscle Development / physiology*
Myocardial Infarction / drug therapy,  enzymology*,  pathology
Myocardium / enzymology,  pathology
Myocytes, Cardiac / drug effects,  enzymology
Neovascularization, Physiologic / drug effects,  physiology*
Ventricular Remodeling / drug effects,  physiology*
Grant Support
ID/Acronym/Agency:
R01 DK085065/DK/NIDDK NIH HHS; R01-HL089405/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 3X2S926L3Z/trichostatin A; EC 3.5.1.98/Histone Deacetylases
Comments/Corrections

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


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