Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 99, Issue -, Pages 167-178Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2016.08.003
Keywords
Histone deacetylases; Epigenetics; NADPH oxidase; Pulmonary artery hypertension
Funding
- NIH [R01HL125926-01A1, 1R01HL124773-01A1, P01 HL101902-01A1, R01HL112640, R01HL126949]
- NSFC [81400033]
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Excessive levels of reactive oxygen species (ROS) and increased expression of NADPH oxidases (Nox) have been proposed to contribute to pulmonary artery hypertension (PAH) and other cardiovascular diseases (CVD). Nox enzymes are major sources of ROS but the mechanisms regulating changes in Nox expression in disease states remain poorly understood. Epigenetics encompasses a number of mechanisms that cells employ to regulate the ability to read and transcribe DNA. Histone acetylation is a prominent example of an epigenetic mechanism regulating the expression of numerous genes by altering chromatin accessibility. The goal of this study was to determine whether inhibition of histone deacetylases (HDAC) affects the expression of Nox isoforms and reduces pulmonary hypertension. In immune cells, we found that multiple HDAC inhibitors robustly decreased Nox2 mRNA and protein expression in a dose-dependent manner concomitant with reduced superoxide production. This effect was not restricted to Nox2 as expression of Noxl, Nox4 and Nox5 was also reduced by HDAC inhibition. Surprisingly, Nox promoterluciferase activity was unchanged in the presence of HDAC inhibitors. In macrophages and lung fibroblasts, ChIP experiments revealed that HDAC inhibitors block the binding of RNA polymerase II and the histone acetyltransferase p300 to the Nox2, Nox4 and Nox5 promoter regions and decrease histones activation marks (H3K4me3 and H3K9ac) at these promoter sites. We further show that the ability of CRISPR-ON to drive transcription of Noxl, Nox2, Nox4 and Nox5 genes is blocked by HDAC inhibitors. In a monocrotaline (MCT) rat model of PAH, multiple HDAC isoforms are upregulated in isolated pulmonary arteries, and HDAC inhibitors attenuate Nox expression in isolated pulmonary arteries and reduce indices of PAH. In conclusion, HDAC inhibitors potently suppress Nox gene expression both in vitro and in vivo via epigenetically regulating chromatin accessibility. (C) 2016 Elsevier B.V. All rights reserved.
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