Document Detail


Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid.
MedLine Citation:
PMID:  22711276     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension, a condition characterized by profound structural remodeling of pulmonary arteries and arterioles.
METHODS AND RESULTS: HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic pulmonary arterial hypertension and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localized increased expression to remodeled vessels in the lung. Both valproic acid, a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (vorinostat), an inhibitor of class I, II, and IV HDACs, mitigated the development of and reduced established hypoxia-induced pulmonary hypertension in the rat. Both valproic acid and suberoylanilide hydroxamic acid inhibited the imprinted highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and platelet-derived growth factor-stimulated growth of human vascular smooth muscle cells in culture. Exposure to valproic acid and suberoylanilide hydroxamic acid was associated with increased levels of p21 and FOXO3 and reduced expression of survivin. The significantly higher levels of expression of cKIT, monocyte chemoattractant protein-1, interleukin-6, stromal-derived factor-1, platelet-derived growth factor-b, and S100A4 in R-cells were downregulated by valproic acid and suberoylanilide hydroxamic acid treatment.
CONCLUSIONS: Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension.
Authors:
Lan Zhao; Chien-Nien Chen; Nabil Hajji; Eduardo Oliver; Emanuele Cotroneo; John Wharton; Daren Wang; Min Li; Timothy A McKinsey; Kurt R Stenmark; Martin R Wilkins
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-18
Journal Detail:
Title:  Circulation     Volume:  126     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-24     Completed Date:  2012-12-03     Revised Date:  2013-10-22    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  455-67     Citation Subset:  AIM; IM    
Affiliation:
Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Rd, London W12 ONN, UK. l.zhao@imperial.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / complications
Cell Proliferation / drug effects
Cells, Cultured
Disease Models, Animal
Histone Deacetylase 1 / antagonists & inhibitors,  metabolism
Histone Deacetylase Inhibitors / pharmacology,  therapeutic use
Histone Deacetylases / drug effects*,  metabolism
Humans
Hydroxamic Acids / pharmacology*,  therapeutic use*
Hypertension, Pulmonary / drug therapy*,  etiology,  metabolism
Lung / drug effects,  metabolism,  pathology
Male
Muscle, Smooth, Vascular / drug effects,  metabolism,  pathology
Platelet-Derived Growth Factor / pharmacology
Pulmonary Artery / drug effects,  metabolism,  pathology
Rats
Rats, Sprague-Dawley
Valproic Acid / pharmacology*,  therapeutic use*
Grant Support
ID/Acronym/Agency:
P01 HL014985/HL/NHLBI NIH HHS; PG/11/28/28844//British Heart Foundation; R01 HL114887/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Platelet-Derived Growth Factor; 149647-78-9/vorinostat; 99-66-1/Valproic Acid; EC 3.5.1.98/HDAC1 protein, human; EC 3.5.1.98/HDAC5 protein, human; EC 3.5.1.98/Hdac1 protein, rat; EC 3.5.1.98/Hdac5 protein, rat; EC 3.5.1.98/Histone Deacetylase 1; EC 3.5.1.98/Histone Deacetylases
Comments/Corrections
Comment In:
Circulation. 2013 Apr 9;127(14):e540   [PMID:  23691553 ]
Circulation. 2013 Apr 9;127(14):e539   [PMID:  23569123 ]

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