{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:09:35Z","timestamp":1780582175301,"version":"3.54.1"},"reference-count":70,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T00:00:00Z","timestamp":1717113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["HL154147"],"award-info":[{"award-number":["HL154147"]}]},{"name":"NIH","award":["AG062375"],"award-info":[{"award-number":["AG062375"]}]},{"name":"NIH","award":["DK138872"],"award-info":[{"award-number":["DK138872"]}]},{"name":"NIH","award":["11PRE7830040"],"award-info":[{"award-number":["11PRE7830040"]}]},{"name":"AHA Predoctoral Fellowship","award":["HL154147"],"award-info":[{"award-number":["HL154147"]}]},{"name":"AHA Predoctoral Fellowship","award":["AG062375"],"award-info":[{"award-number":["AG062375"]}]},{"name":"AHA Predoctoral Fellowship","award":["DK138872"],"award-info":[{"award-number":["DK138872"]}]},{"name":"AHA Predoctoral Fellowship","award":["11PRE7830040"],"award-info":[{"award-number":["11PRE7830040"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Objective: The level of tumor necrosis factor-\u03b1 (TNF-\u03b1) is upregulated during the development of pulmonary vascular remodeling and pulmonary hypertension. A hallmark of pulmonary arterial (PA) remodeling is the excessive proliferation of PA smooth muscle cells (PASMCs). The purpose of this study is to investigate whether TNF-\u03b1 induces PASMC proliferation and explore the potential mechanisms. Methods: PASMCs were isolated from 8-week-old male Sprague-Dawley rats and treated with 0, 20, or 200 ng\/mL TNF-\u03b1 for 24 or 48 h. After treatment, cell number, superoxide production, histone acetylation, DNA methylation, and histone methylation were assessed. Results: TNF-\u03b1 treatment increased NADPH oxidase activity, superoxide production, and cell numbers compared to untreated controls. TNF-\u03b1-induced PASMC proliferation was rescued by a superoxide dismutase mimetic tempol. TNF-\u03b1 treatment did not affect histone acetylation at either dose but did significantly decrease DNA methylation. DNA methyltransferase 1 activity was unchanged by TNF-\u03b1 treatment. Further investigation using QRT-RT-PCR revealed that GADD45-\u03b1, a potential mediator of DNA demethylation, was increased after TNF-\u03b1 treatment. RNAi inhibition of GADD45-\u03b1 alone increased DNA methylation. TNF-\u03b1 impaired the epigenetic mechanism leading to DNA hypomethylation, which can be abolished by a superoxide scavenger tempol. TNF-\u03b1 treatment also decreased H3-K4 methylation. TNF-\u03b1-induced PASMC proliferation may involve the H3-K4 demethylase enzyme, lysine-specific demethylase 1 (LSD1). Conclusions: TNF-\u03b1-induced PASMC proliferation may be partly associated with excessive superoxide formation and histone and DNA methylation.<\/jats:p>","DOI":"10.3390\/antiox13060677","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T10:06:01Z","timestamp":1717409161000},"page":"677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["TNF\u03b1 Induces DNA and Histone Hypomethylation and Pulmonary Artery Smooth Muscle Cell Proliferation Partly via Excessive Superoxide Formation"],"prefix":"10.3390","volume":"13","author":[{"given":"Patrick","family":"Crosswhite","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Department of Human Physiology, Gonzaga University, Spokane, WA 99205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjie","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2119\/molmed.2013.00165","article-title":"Molecular mechanisms of pulmonary arterial remodeling","volume":"20","author":"Crosswhite","year":"2014","journal-title":"Mol. 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