{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:01:37Z","timestamp":1787022097768,"version":"build-2736575974"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007254","name":"creighton university","doi-asserted-by":"publisher","award":["LB692"],"award-info":[{"award-number":["LB692"]}],"id":[{"id":"10.13039\/100007254","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Vascular restenosis often presents as a consequence of injury to the vessel wall, resulting from stenting and other interventional procedures. Such injury to the arteries induces proliferation of Vascular Smooth Muscle Cells (VSMCs), resulting in cellular hyperplasia and restenosis. We and others have previously reported de-novo production of different cytokines and growth factors such as Tumor Necrosis Factor Alpha (TNF-\u03b1) and Insulin like Growth Factor 1 (IGF-1), after vascular injury. As complex as it is, the profuse proliferation of VSMCs appears to be occurring due to several induced factors which initiate molecular mechanisms and exacerbate disease conditions. In many pathological events, the deleterious effects of TNF-\u03b1 and IGF-1 in initiating disease mechanisms was reported. In the present work, we explored whether TNF-\u03b1 and IGF-1 can regulate epigenetic mechanisms that promote proliferation of VSMCs. We investigated the mechanistic roles of proteins which can structurally interact with DNMT1 and initiate cellular pathways that promote proliferation of VSMCs. Our findings here, identify a novel molecular mechanism that is initiated by TNF-\u03b1 and IGF-1. It was previously reported that DNMT1 expression is directly induced by TNF-\u03b1 and IGF-1 treatment and increased\/induced expression of DNMT1 causes silencing of genes that are essential to maintaining cellular homeostasis such as the tumor suppressor genes. We have earlier reported that TNF-\u03b1 and IGF-1 treatment elevates DNMT1 expression in VSMCs and causes increased VSMC proliferation. However, the molecular mechanisms involved were not fully deciphered. Interestingly, in the present study we found that TNF-\u03b1 and IGF-1 treatment failed to elevate DNMT1 expression levels in absence of HDAC2 and HDAC10. Also, while HDAC2 expression was not affected by HDAC10 knockdown, HDAC2 is essentially required for HDAC10 expression. Further, in TNF-\u03b1 and IGF-1 induced epigenetic signaling mechanism, the expression of two important proteins EZH2 and PCNA seem to be regulated in an HDAC2-HDAC10 dependent manner. Our results show an inter-dependence of epigenetic mediators in inducing proliferation in VSMCs. To our knowledge, this is the first report that shows HDAC2 dependent expression of HDAC10, and suggests a novel mechanistic link between DNMT1, HDAC10 and HDAC2 that regulates EZH2 and PCNA to enhance cell proliferation of VSMCs which is the underlying cause for neointimal hyperplasia and restenosis.<\/jats:p>","DOI":"10.1371\/journal.pone.0263190","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T13:44:53Z","timestamp":1644500693000},"page":"e0263190","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Short communication: TNF-\u03b1 and IGF-1 regulates epigenetic mechanisms of HDAC2 and HDAC10"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9631-2540","authenticated-orcid":true,"given":"Wanlin","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5259-5320","authenticated-orcid":true,"given":"Megan E.","family":"Block","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6904-8203","authenticated-orcid":true,"given":"Chandra S.","family":"Boosani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,10]]},"reference":[{"issue":"6","key":"pone.0263190.ref001","doi-asserted-by":"crossref","first-page":"H776","DOI":"10.1152\/ajpheart.00570.2012","article-title":"SOCS3 promotor hypermethylation and STAT3-NF-kappaB interaction downregulate SOCS3 expression in human coronary artery smooth muscle cells","volume":"304","author":"K Dhar","year":"2013","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"6","key":"pone.0263190.ref002","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/S0002-9149(96)00381-5","article-title":"Mechanisms and results of balloon angioplasty for the treatment of in-stent restenosis","volume":"78","author":"R Mehran","year":"1996","journal-title":"Am J Cardiol"},{"issue":"11","key":"pone.0263190.ref003","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1592\/phco.24.16.1554.50955","article-title":"Drug-eluting stents: a mechanical and pharmacologic approach to coronary artery disease.","volume":"24","author":"PP Dobesh","year":"2004","journal-title":"Pharmacotherapy"},{"issue":"5","key":"pone.0263190.ref004","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.jcin.2016.12.002","article-title":"Meta-Analysis of Randomized Clinical Trials Comparing Biodegradable Polymer Drug-Eluting Stent to Second-Generation Durable Polymer Drug-Eluting Stents.","volume":"10","author":"G El-Hayek","year":"2017","journal-title":"JACC Cardiovasc Interv"},{"issue":"24","key":"pone.0263190.ref005","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1056\/NEJMe1703202","article-title":"Device Thrombosis with Bioresorbable Scaffolds","volume":"376","author":"D. 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