{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T18:46:44Z","timestamp":1793126804450,"version":"4.5.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,19]],"date-time":"2017-05-19T00:00:00Z","timestamp":1495152000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,19]],"date-time":"2017-05-19T00:00:00Z","timestamp":1495152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Activation of peroxisome proliferator-activated receptor gamma (PPAR\u03b3) in the cerebrovascular endothelium is a key suppressor of post-stroke brain damage. However, the role of PPAR\u03b3\u2019s co-regulators during cerebral ischemia remains largely unknown. Here, we show that the transcription factor IRF6 is a novel PPAR\u03b3 co-regulator that directly binds to and suppresses PPAR\u03b3 activity in murine cerebrovascular endothelial cells. Moreover, IRF6 was also revealed to be a transcriptional target of PPAR\u03b3 suppression, with PPAR\u03b3 silencing significantly promoting IRF6 expression in cerebrovascular endothelial cells. In addition, IRF6 silencing significantly promoted pioglitazone\u2019s cytoprotective effects in ischemic murine cerebrovascular endothelial cells. Mechanistically, IRF6 significantly suppressed PPAR\u03b3\u2019s transcriptional inhibition of the ischemia-induced, pro-apoptotic microRNA miR-106a. In conclusion, we identified IRF6 as a novel PPAR\u03b3 co-suppressor that serves a key role in suppressing PPAR\u03b3-mediated cerebrovascular endothelial cytoprotection following ischemia. Further investigation into IRF6 and other PPAR\u03b3 co-regulators should provide additional insights into PPAR\u03b3\u2019s cytoprotective role in the cerebrovascular endothelium following stroke.<\/jats:p>","DOI":"10.1038\/s41598-017-02095-3","type":"journal-article","created":{"date-parts":[[2017,5,15]],"date-time":"2017-05-15T09:39:45Z","timestamp":1494841185000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Transcription Factor IRF6 Co-Represses PPAR\u03b3-Mediated Cytoprotection in Ischemic Cerebrovascular Endothelial Cells"],"prefix":"10.1038","volume":"7","author":[{"given":"Rongzhong","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zicheng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lehua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingsheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,19]]},"reference":[{"key":"2095_CR1","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0140-6736(13)61953-4","volume":"383","author":"VL Feigin","year":"2014","unstructured":"Feigin, V. L. et al. Global and regional burden of stroke during 1990\u20132010: findings from the Global Burden of Disease Study 2010. The Lancet \n                           383, 245\u2013255, doi:10.1016\/S0140-6736(13)61953-4 (2014).","journal-title":"The Lancet"},{"key":"2095_CR2","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/S1474-4422(16)00114-9","volume":"15","author":"\u00c1 Chamorro","year":"2016","unstructured":"Chamorro, \u00c1., Dirnagl, U., Urra, X. & Planas, A. M. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. The Lancet Neurology \n                           15, 869\u2013881, doi:10.1016\/S1474-4422(16)00114-9 (2016).","journal-title":"The Lancet Neurology"},{"key":"2095_CR3","doi-asserted-by":"publisher","first-page":"H39","DOI":"10.1152\/ajpheart.00490.2015","volume":"310","author":"M Mukohda","year":"2016","unstructured":"Mukohda, M. et al. Endothelial PPAR-\u03b3 provides vascular protection from IL-1\u03b2-induced oxidative stress. American Journal of Physiology-Heart and Circulatory Physiology \n                           310, H39\u2013H48, doi:10.1152\/ajpheart.00490.2015 (2016).","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"2095_CR4","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1161\/ATVBAHA.115.305378","volume":"35","author":"H Jin","year":"2015","unstructured":"Jin, H. et al. Endothelial PPAR-\u03b3 protects against vascular thrombosis by downregulating P-selectin expression. Arteriosclerosis, thrombosis, and vascular biology \n                           35, 838\u2013844, doi:10.1161\/ATVBAHA.115.305378 (2015).","journal-title":"Arteriosclerosis, thrombosis, and vascular biology"},{"key":"2095_CR5","doi-asserted-by":"publisher","first-page":"6186","DOI":"10.1523\/JNEUROSCI.5857-08.2009","volume":"29","author":"X Zhao","year":"2009","unstructured":"Zhao, X. et al. Neuronal PPAR\u03b3 deficiency increases susceptibility to brain damage after cerebral ischemia. The Journal of Neuroscience \n                           29, 6186\u20136195, doi:10.1523\/JNEUROSCI.5857-08.2009 (2009).","journal-title":"The Journal of Neuroscience"},{"key":"2095_CR6","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/jcbfm.2009.185","volume":"30","author":"Q Guo","year":"2010","unstructured":"Guo, Q., Wang, G. & Namura, S. Fenofibrate improves cerebral blood flow after middle cerebral artery occlusion in mice. Journal of Cerebral Blood Flow & Metabolism \n                           30, 70\u201378, doi:10.1038\/jcbfm.2009.185 (2010).","journal-title":"Journal of Cerebral Blood Flow & Metabolism"},{"key":"2095_CR7","doi-asserted-by":"publisher","first-page":"CD010693","DOI":"10.1002\/14651858.CD010693.pub3","volume":"10","author":"J Liu","year":"2015","unstructured":"Liu, J. & Wang, L. N. Peroxisome proliferator\u2010activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. Cochrane Database of Systematic Reviews \n                           10, CD010693, doi:10.1002\/14651858.CD010693.pub3 (2015).","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"2095_CR8","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1097\/MNH.0000000000000103","volume":"24","author":"P Ketsawatsomkron","year":"2015","unstructured":"Ketsawatsomkron, P. & Sigmund, C. D. Molecular mechanisms regulating vascular tone by peroxisome proliferator activated receptor gamma. Current opinion in nephrology and hypertension \n                           24, 123\u2013130, doi:10.1097\/MNH.0000000000000103 (2015).","journal-title":"Current opinion in nephrology and hypertension"},{"key":"2095_CR9","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1093\/brain\/awt002","volume":"136","author":"K-J Yin","year":"2013","unstructured":"Yin, K.-J. et al. KLF11 mediates PPAR\u03b3 cerebrovascular protection in ischaemic stroke. Brain \n                           136, 1274\u20131287, doi:10.1093\/brain\/awt002 (2013).","journal-title":"Brain"},{"key":"2095_CR10","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.molmed.2011.07.007","volume":"17","author":"E Mangold","year":"2011","unstructured":"Mangold, E., Ludwig, K. U. & N\u00f6then, M. M. Breakthroughs in the genetics of orofacial clefting. Trends in molecular medicine \n                           17, 725\u2013733, doi:10.1016\/j.molmed.2011.07.007 (2011).","journal-title":"Trends in molecular medicine"},{"key":"2095_CR11","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/ng985","volume":"32","author":"S Kondo","year":"2002","unstructured":"Kondo, S. et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature genetics \n                           32, 285\u2013289, doi:10.1038\/ng985 (2002).","journal-title":"Nature genetics"},{"key":"2095_CR12","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1038\/ng1903","volume":"38","author":"CR Ingraham","year":"2006","unstructured":"Ingraham, C. R. et al. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nature genetics \n                           38, 1335\u20131340, doi:10.1038\/ng1903 (2006).","journal-title":"Nature genetics"},{"key":"2095_CR13","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12675","author":"EJ Leslie","year":"2015","unstructured":"Leslie, E. J. et al. IRF6 mutation screening in non\u2010syndromic orofacial clefting: analysis of 1521 families. Clinical genetics. doi:10.1111\/cge.12675 (2015).","journal-title":"Clinical genetics"},{"key":"2095_CR14","doi-asserted-by":"publisher","first-page":"e0132757","DOI":"10.1371\/journal.pone.0132757","volume":"10","author":"T Zengin","year":"2015","unstructured":"Zengin, T., Ekinci, B., Kucukkose, C. & Yalcin-Ozuysal, O. IRF6 is involved in the regulation of cell proliferation and transformation in MCF10A cells downstream of Notch signaling. 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Scientific reports \n                           5, doi:10.1038\/srep12791 (2015).","DOI":"10.1038\/srep12791"},{"key":"2095_CR17","doi-asserted-by":"publisher","first-page":"6398","DOI":"10.1523\/JNEUROSCI.0780-10.2010","volume":"30","author":"K-J Yin","year":"2010","unstructured":"Yin, K.-J. et al. Peroxisome proliferator-activated receptor \u03b4 regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. Journal of Neuroscience \n                           30, 6398\u20136408, doi:10.1523\/JNEUROSCI.0780-10.2010 (2010).","journal-title":"Journal of Neuroscience"},{"key":"2095_CR18","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.1523\/JNEUROSCI.5103-05.2006","volume":"26","author":"K-J Yin","year":"2006","unstructured":"Yin, K.-J. et al. Protein phosphatase 2A regulates Bim expression via the Akt\/FKHRL1 signaling pathway in amyloid-\u03b2 peptide-induced cerebrovascular endothelial cell death. The Journal of neuroscience \n                           26, 2290\u20132299, doi:10.1523\/JNEUROSCI.5103-05.2006 (2006).","journal-title":"The Journal of neuroscience"},{"key":"2095_CR19","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/1476-4598-7-90","volume":"7","author":"YY Zaytseva","year":"2008","unstructured":"Zaytseva, Y. Y., Wang, X., Southard, R. C., Wallis, N. K. & Kilgore, M. W. Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells. Molecular Cancer \n                           7, 90, doi:10.1186\/1476-4598-7-90 (2008).","journal-title":"Molecular Cancer"},{"key":"2095_CR20","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1038\/mt.2008.104","volume":"16","author":"J Shen","year":"2008","unstructured":"Shen, J. et al. MicroRNAs regulate ocular neovascularization. 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Brain research \n                           975, 10\u201321, doi:10.1016\/S0006-8993(03)02515-0 (2003).","journal-title":"Brain research"},{"key":"2095_CR25","doi-asserted-by":"publisher","unstructured":"Zhao, X. & Aronowski, J. In Immunological Mechanisms and Therapies in Brain Injuries and Stroke Vol. 6 Springer Series in Translational Stroke Research (eds Jun Chen, Xiaoming Hu, Mary Stenzel-Poore & John H. Zhang) 301\u2013320, doi:10.1007\/978-1-4614-8915-3_17 (Springer, 2014).","DOI":"10.1007\/978-1-4614-8915-3_17"},{"key":"2095_CR26","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.expneurol.2012.09.003","volume":"238","author":"J Culman","year":"2012","unstructured":"Culman, J. et al. Treatment of rats with pioglitazone in the reperfusion phase of focal cerebral ischemia: a preclinical stroke trial. Experimental neurology \n                           238, 243\u2013253, doi:10.1016\/j.expneurol.2012.09.003 (2012).","journal-title":"Experimental neurology"},{"key":"2095_CR27","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1056\/NEJMoa1506930","volume":"374","author":"WN Kernan","year":"2016","unstructured":"Kernan, W. N. et al. Pioglitazone after ischemic stroke or transient ischemic attack. New England Journal of Medicine \n                           374, 1321\u20131331, doi:10.1056\/NEJMoa1506930 (2016).","journal-title":"New England Journal of Medicine"},{"key":"2095_CR28","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1161\/01.STR.0000257974.06317.49","volume":"38","author":"R Wilcox","year":"2007","unstructured":"Wilcox, R. et al. Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke Results From PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). 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Nature Reviews Genetics \n                           11, 109\u2013123, doi:10.1038\/nrg2736 (2010).","journal-title":"Nature Reviews Genetics"},{"key":"2095_CR31","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1101\/gad.1263305","volume":"19","author":"H-P Guan","year":"2005","unstructured":"Guan, H.-P., Ishizuka, T., Chui, P. C., Lehrke, M. & Lazar, M. A. Corepressors selectively control the transcriptional activity of PPAR\u03b3 in adipocytes. Genes & development \n                           19, 453\u2013461, doi:10.1101\/gad.1263305 (2005).","journal-title":"Genes & development"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02095-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02095-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02095-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T04:28:54Z","timestamp":1671769734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02095-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,19]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["2095"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-02095-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,19]]},"assertion":[{"value":"13 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2150"}}