title: Inhibition of histone deacetylase causes emphysema.
abstract: In patients with chronic obstructive pulmonary disease (COPD), histone deacetylase (HDAC) expression and activity are reduced in the lung tissue. However, whether HDAC activity controls the maintenance of the lung alveolar septal structures has not been investigated. To explore the consequences of HDAC inhibition and address the question of whether HDAC inhibition causes lung cell apoptosis and emphysema, male Sprague-Dawley rats and human pulmonary microvascular endothelial cells (HPMVEC) were treated with trichostatin A (TSA), a specific inhibitor of HDACs. Chronic TSA treatment increased the alveolar air space area, mean linear intercept, and the number of caspase-3-positive cells in rat lungs. TSA suppressed hypoxia-inducible factor-1α (HIF-1α), VEGF, and lysyl oxidase (LOX) and increased microtubule-associated protein-1 light chain 3 (LC3), p53, and miR34a microRNA expression in both rat lungs and cultured HPMVEC. Gene silencing of HDAC2 using small interfering RNA (siRNA) in cultured HPMVEC resulted in the suppression of HIF-1α, VEGF, and LOX and an increase of p53 expression. These data indicate that HDAC inhibition causes emphysema and that HDAC-dependent mechanisms contribute to the maintenance of the adult lung structure. Our results also suggest that the increase in apoptosis, as a consequence of HDAC inhibition, is associated with decreased VEGF and HIF-1α expression.
authors.affiliation: Pulmonary and Critical Care Medicine Division, Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth Univ., Richmond, VA 23284, USA.
authors.forename: Shiro
authors.initials: S
authors.lastname: Mizuno
authors.forename: Masanori
authors.initials: M
authors.lastname: Yasuo
authors.forename: Herman J
authors.initials: HJ
authors.lastname: Bogaard
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.forename: Ramesh
authors.initials: R
authors.lastname: Natarajan
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D055806:Microvessels / Q000473:pathology; D008954:Models, Biological; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000473:pathology*; D020871:RNA Stability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; C012589:trichostatin A; D006655:Histone Deacetylases