{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T21:50:40Z","timestamp":1788817840083,"version":"build-2803163510"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T00:00:00Z","timestamp":1706745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P50AR060780-07"],"award-info":[{"award-number":["P50AR060780-07"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1R61AR076819-01"],"award-info":[{"award-number":["1R61AR076819-01"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019921","name":"National Scleroderma Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019921","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To define the functional relevance of H19 X-linked (H19X) co-expressed long non-coding RNA (lncRNA) in endothelial cell (EC) activation as a key process in SSc vasculopathy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>H19X expression in SSc skin biopsies was analysed from single-cell RNA sequencing (scRNA-seq) data. Differential expression and pathway enrichment analysis between cells expressing (H19Xpos) and non-expressing H19X (H19Xneg) cells was performed. H19X function was investigated in human dermal microvascular ECs (HDMECs) by silencing. H19X and EC adhesion molecule levels were analysed by real-time quantitative PCR and western blot after stimulation with pro-inflammatory cytokines. Cytoskeletal rearrangements were analysed by fluorescent staining. Endothelial adhesion was evaluated by co-culture of HDMECs and fluorescent-labelled peripheral blood mononuclear cells (PBMCs). Shedding vascular cell adhesion protein 1 (VCAM1) was evaluated by ELISA on HDMEC supernatant.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The scRNA-seq data showed significant upregulation of H19X in SSc compared with healthy ECs. In HDMECs, H19X was consistently induced by IFN type I and II. H19X knockdown lead to a significant decrease in the mRNA of several adhesion molecules. In particular, VCAM1 was significantly reduced at the protein and mRNA levels. Co-expression analysis of the scRNA-seq data confirmed higher expression of VCAM1 in H19Xpos ECs. ECs were also strongly associated with the \u2018cell adhesion molecule\u2019 pathway. Moreover, the VCAM1 downstream pathway displayed less activation following H19X knockdown. Contractility of HDMECs, PBMC adhesion to HDMECs and VCAM1 shedding were also reduced following H19X knockdown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>lncRNA H19X may contribute to EC activation in SSc vasculopathy, acting as a regulator of expression of adhesion molecules in ECs.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/rheumatology\/keae034","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T14:31:30Z","timestamp":1706884290000},"page":"2846-2855","source":"Crossref","is-referenced-by-count":2,"title":["Long non-coding RNA H19X as a regulator of mononuclear cell adhesion to the endothelium in systemic sclerosis"],"prefix":"10.1093","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9947-4059","authenticated-orcid":false,"given":"Francesca","family":"Tirelli","sequence":"first","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich , Zurich,","place":["Switzerland"]},{"name":"Rheumatology Unit, Department of Woman and Child Health, University Hospital of Padua , Padua,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5157-3808","authenticated-orcid":false,"given":"Elena","family":"Pachera","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich , Zurich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Gm\u00fcr","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich , Zurich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Lafyatis","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh , Pittsburgh, Pennsylvania,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh , Pittsburgh, Pennsylvania,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2479-3485","authenticated-orcid":false,"given":"Francesco","family":"Zulian","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Woman and Child Health, University Hospital of Padua , Padua,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Camarillo Retamosa","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich , Zurich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Kania","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich , Zurich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0546-8310","authenticated-orcid":false,"given":"Oliver","family":"Distler","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich , Zurich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,2,1]]},"reference":[{"key":"2024100107540336700_keae034-B1","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1002\/art.37988","article-title":"Review: evidence that systemic sclerosis is a vascular disease","volume":"65","author":"Matucci-Cerinic","year":"2013","journal-title":"Arthritis Rheum"},{"key":"2024100107540336700_keae034-B2","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1097\/BOR.0000000000000112","article-title":"Endothelial dysfunction in systemic sclerosis","volume":"26","author":"Altorok","year":"2014","journal-title":"Curr Opin Rheumatol"},{"key":"2024100107540336700_keae034-B3","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.autrev.2017.05.024","article-title":"The role of endothelial cells in the vasculopathy of systemic sclerosis: a systematic review","volume":"16","author":"Mostmans","year":"2017","journal-title":"Autoimmun Rev"},{"key":"2024100107540336700_keae034-B4","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00281-015-0505-5","article-title":"Vasculopathy in scleroderma","volume":"37","author":"Asano","year":"2015","journal-title":"Semin Immunopathol"},{"key":"2024100107540336700_keae034-B5","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/nrg3074","article-title":"Non-coding RNAs in human disease","volume":"12","author":"Esteller","year":"2011","journal-title":"Nat Rev Genet"},{"key":"2024100107540336700_keae034-B6","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/nrrheum.2017.162","article-title":"The role of long non-coding RNAs in rheumatic diseases","volume":"13","author":"Tang","year":"2017","journal-title":"Nat Rev Rheumatol"},{"key":"2024100107540336700_keae034-B7","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.4110\/in.2019.19.e4","article-title":"Potential implications of long noncoding RNAs in autoimmune diseases","volume":"19","author":"Hur","year":"2019","journal-title":"Immune Netw"},{"key":"2024100107540336700_keae034-B8","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1172\/JCI135439","article-title":"Long noncoding RNA H19X is a key mediator of TGF-\u03b2\u2013driven fibrosis","volume":"130","author":"Pachera","year":"2020","journal-title":"J Clin Invest"},{"key":"2024100107540336700_keae034-B9","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1136\/annrheumdis-2021-220209","article-title":"Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis","volume":"80","author":"Gaydosik","year":"2021","journal-title":"Ann Rheum Dis"},{"key":"2024100107540336700_keae034-B10","first-page":"202","article-title":"Scleroderma (systemic sclerosis): classification, subsets and pathogenesis","volume":"15","author":"LeRoy","year":"1988","journal-title":"J Rheumatol"},{"key":"2024100107540336700_keae034-B11","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1002\/1529-0131(200011)43:11<2437::AID-ANR10>3.0.CO;2-U","article-title":"Severe organ involvement in systemic sclerosis with diffuse scleroderma","volume":"43","author":"Steen","year":"2000","journal-title":"Arthritis Rheum"},{"key":"2024100107540336700_keae034-B12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2024100107540336700_keae034-B13","doi-asserted-by":"crossref","first-page":"8235","DOI":"10.1021\/bi300925r","article-title":"Distinct sites within the vascular cell adhesion molecule-1 (VCAM-1) cytoplasmic domain regulate VCAM-1 activation of calcium fluxes versus Rac1 during leukocyte transendothelial migration","volume":"51","author":"Marchese","year":"2012","journal-title":"Biochemistry"},{"key":"2024100107540336700_keae034-B14","doi-asserted-by":"crossref","first-page":"4738","DOI":"10.1111\/jcmm.14344","article-title":"LncRNA MIR503HG inhibits cell migration and invasion via miR-103\/OLFM4 axis in triple negative breast cancer","volume":"23","author":"Fu","year":"2019","journal-title":"J Cell Mol Med"},{"key":"2024100107540336700_keae034-B15","doi-asserted-by":"crossref","first-page":"10821","DOI":"10.1002\/jcb.28373","article-title":"lncRNA MIR503HG functioned as a tumor suppressor and inhibited cell proliferation, metastasis and epithelial-mesenchymal transition in bladder cancer","volume":"120","author":"Qiu","year":"2019","journal-title":"J Cell Biochem"},{"key":"2024100107540336700_keae034-B16","doi-asserted-by":"crossref","first-page":"112205","DOI":"10.1016\/j.yexcr.2020.112205","article-title":"Long non-coding RNA MIR503HG inhibits the proliferation, migration and invasion of colon cancer cells via miR-107\/Par4 axis","volume":"395","author":"Han","year":"2020","journal-title":"Exp Cell Res"},{"key":"2024100107540336700_keae034-B17","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.2147\/CMAR.S227348","article-title":"LncRNA MIR503HG inhibits non-small cell lung cancer cell proliferation by inducing cell cycle arrest through the downregulation of cyclin D1","volume":"12","author":"Xu","year":"2020","journal-title":"Cancer Manag Res"},{"key":"2024100107540336700_keae034-B18","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1161\/CIRCRESAHA.120.318124","article-title":"MIR503HG loss promotes endothelial-to-mesenchymal transition in vascular disease","volume":"128","author":"Monteiro","year":"2021","journal-title":"Circ Res"},{"key":"2024100107540336700_keae034-B19","doi-asserted-by":"crossref","first-page":"D884","DOI":"10.1093\/nar\/gkaa942","article-title":"Ensembl 2021","volume":"49","author":"Howe","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"2024100107540336700_keae034-B20","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1136\/ard.2011.150326","article-title":"Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway","volume":"70","author":"Higgs","year":"2011","journal-title":"Ann Rheum Dis"},{"key":"2024100107540336700_keae034-B21","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1136\/annrheumdis-2015-207392","article-title":"The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis","volume":"75","author":"Brkic","year":"2016","journal-title":"Ann Rheum Dis"},{"key":"2024100107540336700_keae034-B22","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1038\/jid.2010.200","article-title":"Poly(I: c) drives type I IFN- and TGFbeta-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis","volume":"130","author":"Farina","year":"2010","journal-title":"J Invest Dermatol"},{"key":"2024100107540336700_keae034-B23","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1046\/j.1365-2249.1999.00842.x","article-title":"Increased interferon-gamma (IFN-gamma) levels produced in vitro by alloactivated T lymphocytes in systemic sclerosis and Raynaud's phenomenon","volume":"116","author":"Molteni","year":"1999","journal-title":"Clin Exp Immunol"},{"key":"2024100107540336700_keae034-B24","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.imlet.2017.10.011","article-title":"Targeting interferons as a strategy for systemic sclerosis treatment","volume":"195","author":"Ciechomska","year":"2018","journal-title":"Immunol Lett"},{"key":"2024100107540336700_keae034-B25","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1136\/jcp.2004.019224","article-title":"Alterations of mononuclear inflammatory cells, CD4\/CD8+ T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis","volume":"58","author":"Hussein","year":"2005","journal-title":"J Clin Pathol"},{"key":"2024100107540336700_keae034-B26","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1517\/17425255.2014.970165","article-title":"Pharmacogenetics of etanercept: role of TNF-\u03b1 gene polymorphisms in improving its efficacy","volume":"10","author":"Murdaca","year":"2014","journal-title":"Expert Opin Drug Met"},{"key":"2024100107540336700_keae034-B27","doi-asserted-by":"crossref","first-page":"C343","DOI":"10.1152\/ajpcell.00048.2003","article-title":"VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration","volume":"285","author":"van Wetering","year":"2003","journal-title":"Am J Physiol Cell Physiol"},{"key":"2024100107540336700_keae034-B28","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.3390\/ijms19041057","article-title":"Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer","volume":"19","author":"Kong","year":"2018","journal-title":"Int J Mol Sci"},{"key":"2024100107540336700_keae034-B29","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1159\/000163802","article-title":"In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease","volume":"61","author":"Koch","year":"1993","journal-title":"Pathobiology"},{"key":"2024100107540336700_keae034-B30","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1089\/ars.2010.3522","article-title":"Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants","volume":"15","author":"Cook-Mills","year":"2011","journal-title":"Antioxid Redox Signal"},{"key":"2024100107540336700_keae034-B31","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1002\/1529-0131(200005)43:5<1085::AID-ANR19>3.0.CO;2-7","article-title":"Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1","volume":"43","author":"Andersen","year":"2000","journal-title":"Arthritis Rheum"},{"key":"2024100107540336700_keae034-B32","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1053\/sarh.2002.50011","article-title":"Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis","volume":"32","author":"Cerinic","year":"2003","journal-title":"Semin Arthritis Rheum"},{"key":"2024100107540336700_keae034-B33","doi-asserted-by":"crossref","first-page":"46621","DOI":"10.1074\/jbc.M408877200","article-title":"p21-activated kinase regulates endothelial permeability through modulation of contractility","volume":"279","author":"Stockton","year":"2004","journal-title":"J Biol Chem"}],"container-title":["Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/rheumatology\/advance-article-pdf\/doi\/10.1093\/rheumatology\/keae034\/56609712\/keae034.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/rheumatology\/article-pdf\/63\/10\/2846\/59432695\/keae034.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/rheumatology\/article-pdf\/63\/10\/2846\/59432695\/keae034.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T07:55:14Z","timestamp":1727769314000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/rheumatology\/article\/63\/10\/2846\/7596628"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,1]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,2,1]]},"published-print":{"date-parts":[[2024,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/rheumatology\/keae034","relation":{},"ISSN":["1462-0324","1462-0332"],"issn-type":[{"value":"1462-0324","type":"print"},{"value":"1462-0332","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,10]]},"published":{"date-parts":[[2024,2,1]]}}}