{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T08:36:12Z","timestamp":1779179772080,"version":"3.51.4"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:00:00Z","timestamp":1524528000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"Objective<\/jats:title>NKX<\/jats:styled-content>2\u20105 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down\u2010regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX<\/jats:styled-content>2\u20105 expression in diseased vessels, such as systemic sclerosis (scleroderma; SS<\/jats:styled-content>c)\u2013associated pulmonary hypertension (PH<\/jats:styled-content>), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications.<\/jats:p><\/jats:sec>Methods<\/jats:title>We explored NKX<\/jats:styled-content>2\u20105 expression in biopsy samples from patients with SS<\/jats:styled-content>c\u2010associated PH<\/jats:styled-content> and in pulmonary artery smooth muscle cells (PASMC<\/jats:styled-content>s) from patients with scleroderma. Disease\u2010associated putative functional single\u2010nucleotide polymorphisms (SNP<\/jats:styled-content>s) at the NKX<\/jats:styled-content>2-5<\/jats:italic> locus were cloned and studied in reporter gene assays. SNP<\/jats:styled-content> function was further examined through protein\u2013DNA<\/jats:styled-content> binding assays, chromatin immunoprecipitation assays, and RNA<\/jats:styled-content> silencing analyses.<\/jats:p><\/jats:sec>Results<\/jats:title>Increased NKX<\/jats:styled-content>2\u20105 expression in biopsy samples from patients with SS<\/jats:styled-content>c\u2010associated PH<\/jats:styled-content> was localized to remodeled vessels and PASMC<\/jats:styled-content>s. Meta\u2010analysis of 2 independent scleroderma cohorts revealed an association of rs3131917 with scleroderma (P<\/jats:italic> = 0.029). We demonstrated that disease\u2010associated SNP<\/jats:styled-content>s are located in a novel functional enhancer, which increases NKX<\/jats:styled-content>2-5<\/jats:italic> transcriptional activity through the binding of GATA<\/jats:styled-content>\u20106, c\u2010Jun, and myocyte\u2010specific enhancer factor 2C. We also characterized an activator\/coactivator transcription\u2010enhancer factor domain 1 (TEAD<\/jats:styled-content>1)\/Yes\u2010associated protein 1 (YAP<\/jats:styled-content>1) complex, which was bound at rs3095870, another functional SNP<\/jats:styled-content>, with TEAD<\/jats:styled-content>1 binding the risk allele and activating the transcription of NKX<\/jats:styled-content>2-5<\/jats:italic>.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>NKX<\/jats:styled-content>2-5<\/jats:italic> is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX<\/jats:styled-content>2-5<\/jats:italic> transcriptional activation in PASMC<\/jats:styled-content>s through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX<\/jats:styled-content>2\u20105 activation in cardiovascular disease characterized by vascular remodeling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40419","type":"journal-article","created":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T19:06:40Z","timestamp":1516216000000},"page":"920-931","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Molecular Basis for Dysregulated Activation of NKX<\/scp>2\u20105 in the Vascular Remodeling of Systemic Sclerosis"],"prefix":"10.1002","volume":"70","author":[{"given":"Athina","family":"Dritsoula","sequence":"first","affiliation":[{"name":"University College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Papaioannou","sequence":"additional","affiliation":[{"name":"University College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra 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