Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension

Eva Nozik-Grayck; Crystal Woods; Robert S Stearman; Sujatha Venkataraman; Bradley S Ferguson; Kalin Swain; Russell P Bowler; Mark W Geraci; Kaori Ihida-Stansbury; Kurt R Stenmark; Timothy A McKinsey; Frederick E Domann

doi:10.1152/ajplung.00263.2015

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Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension

Journal article

Open access

Peer reviewed

Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension

Eva Nozik-Grayck, Crystal Woods, Robert S Stearman, Sujatha Venkataraman, Bradley S Ferguson, Kalin Swain, Russell P Bowler, Mark W Geraci, Kaori Ihida-Stansbury, Kurt R Stenmark, …

American journal of physiology. Lung cellular and molecular physiology, Vol.311(1), pp.L124-L134

07/01/2016

DOI: 10.1152/ajplung.00263.2015

PMCID: PMC4967185

PMID: 27233998

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Abstract

Epigenetic mechanisms, including DNA methylation and histone acetylation, regulate gene expression in idiopathic pulmonary arterial hypertension (IPAH). These mechanisms can modulate expression of extracellular superoxide dismutase (SOD3 or EC-SOD), a key vascular antioxidant enzyme, and loss of vascular SOD3 worsens outcomes in animal models of pulmonary arterial hypertension. We hypothesized that SOD3 gene expression is decreased in patients with IPAH due to aberrant DNA methylation and/or histone deacetylation. We used lung tissue and pulmonary artery smooth muscle cells (PASMC) from subjects with IPAH at transplantation and from failed donors (FD). Lung SOD3 mRNA expression and activity was decreased in IPAH vs. FD. In contrast, mitochondrial SOD (Mn-SOD or SOD2) protein expression was unchanged and intracellular SOD activity was unchanged. Using bisulfite sequencing in genomic lung or PASMC DNA, we found the methylation status of the SOD3 promoter was similar between FD and IPAH. Furthermore, treatment with 5-aza-2'-deoxycytidine did not increase PASMC SOD3 mRNA, suggesting DNA methylation was not responsible for PASMC SOD3 expression. Though total histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity, acetylated histones, and acetylated SP1 were similar between IPAH and FD, treatment with two selective class I HDAC inhibitors increased SOD3 only in IPAH PASMC. Class I HDAC3 siRNA also increased SOD3 expression. Trichostatin A, a pan-HDAC inhibitor, decreased proliferation in IPAH, but not in FD PASMC. These data indicate that histone deacetylation, specifically via class I HDAC3, decreases SOD3 expression in PASMC and HDAC inhibitors may protect IPAH in part by increasing PASMC SOD3 expression.

Gene Expression

Promoter Regions, Genetic

Superoxide Dismutase - genetics

Myocytes, Smooth Muscle - enzymology

Humans

Middle Aged

Cells, Cultured

Rats

Male

Young Adult

Muscle, Smooth, Vascular - pathology

Animals

Adult

Female

Histone Deacetylase Inhibitors - pharmacology

Protein Processing, Post-Translational

Acetylation

Histones - metabolism

Enzyme Repression

Hypertension, Pulmonary - enzymology

Superoxide Dismutase - metabolism

Details

Title: Subtitle: Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension
Creators: Eva Nozik-Grayck - Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado; Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Center, Aurora, Colorado; eva.grayck@ucdenver.edu
Crystal Woods - Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado; Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Center, Aurora, Colorado
Robert S Stearman - Department of Medicine, Indiana University, Indianapolis, Indiana; and
Sujatha Venkataraman - Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado
Bradley S Ferguson - Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado
Kalin Swain - Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado; Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Center, Aurora, Colorado
Russell P Bowler - Department of Medicine, National Jewish Hospital, Denver, Colorado
Mark W Geraci - Department of Medicine, Indiana University, Indianapolis, Indiana; and
Kaori Ihida-Stansbury - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Kurt R Stenmark - Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado; Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Center, Aurora, Colorado; Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado
Timothy A McKinsey - Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado
Frederick E Domann - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: American journal of physiology. Lung cellular and molecular physiology, Vol.311(1), pp.L124-L134
DOI: 10.1152/ajplung.00263.2015
PMID: 27233998
PMCID: PMC4967185
NLM abbreviation: Am J Physiol Lung Cell Mol Physiol
ISSN: 1040-0605
eISSN: 1522-1504
Publisher: American Physiological Society; United States
Grant note: R01 HL086680 / NHLBI NIH HHS T32 HL007171 / NHLBI NIH HHS R01 HL114887 / NHLBI NIH HHS R21 AG043822 / NIA NIH HHS R03 HL110783 / NHLBI NIH HHS R01 HL116848 / NHLBI NIH HHS F32 HL124893 / NHLBI NIH HHS P01 HL014985 / NHLBI NIH HHS R01 HL127240 / NHLBI NIH HHS
Language: English
Date published: 07/01/2016
Academic Unit: Pathology; Surgery; Radiation Oncology
Record Identifier: 9984047725902771

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