Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats

Iyer, Abishek, Fenning, Andrew, Lim, Junxian, Le, Giang T, Reid, Robert C, Halili, Maria A, Fairlie, David P and Brown, Lindsay (2010) Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats. British Journal of Pharmacology, 159 7: 1408-1417.


Author Iyer, Abishek
Fenning, Andrew
Lim, Junxian
Le, Giang T
Reid, Robert C
Halili, Maria A
Fairlie, David P
Brown, Lindsay
Title Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats
Journal name British Journal of Pharmacology  (ERA 2012 Listed)    (ERA 2010 Rank A*)   Check publisher's open access policy
Publication date 2010-04
Sub-type Article
DOI 10.1111/j.1476-5381.2010.00637.x
Volume number 159
Issue number 7
ISSN 0007-1188; 1476-5381; 0366-0826; 1359-5075
Start page 1408
End page 1417
Total pages 10
Editor J. C. McGrath
Place of publication London, U.K.
Publisher John Wiley & Sons
Collection year 2011
Language eng
Subject C1
920103 Cardiovascular System and Diseases
0601 Biochemistry and Cell Biology
Formatted abstract Background and purpose: Histone deacetylases (HDACs) silence genes by deacetylating lysine residues in histones and other proteins. HDAC inhibitors represent a new class of compounds with anti-inflammatory activity. This study investigated whether treatment with a broad spectrum HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), would prevent cardiac fibrosis, part of the cardiovascular remodelling in deoxycorticosterone acetate (DOCA)-salt rats.

Experimental approach: Control and DOCA-salt rats were treated with SAHA (25 mg·kg−1·day−1 s.c.) for 32 days. Changes in cardiovascular structure and function were assessed by blood pressure in vivo and in Langendorff perfused hearts, ventricular papillary muscle and in aortic rings in vitro. Left ventricular collagen deposition was assessed by histology.

Key results: Administration of SAHA to DOCA-salt rats attenuated the following parameters: the increased concentration of over 20 pro-inflammatory cytokines in plasma, increased inflammatory cell infiltration and interstitial collagen deposition, increased passive diastolic stiffness in perfused hearts, prolongation of action potential duration at 20% and 90% of repolarization in papillary muscle, development of left ventricular hypertrophy, systolic hypertension and changes in vascular dysfunction.

Conclusions and implications: The HDAC inhibitor, SAHA, attenuated the cardiovascular remodelling associated with DOCA-salt hypertensive rats and improved cardiovascular structure and function, especially fibrosis, in the heart and blood vessels, possibly by suppressing inflammation. Control of cardiac histone or non-histone protein acetylation is a potential therapeutic approach to preventing cardiac remodelling, especially cardiac fibrosis.
© 2010 The British Pharmacological Society.
Keyword Histone acetyltransferase
Histone deacetylase inhibitor
Cardiac remodelling
Hypertrophy
Fibrosis
Hypertension
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Sun, 11 Apr 2010, 00:07:23 EST