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When dysregulated, these processes contribute to the development of various lung and cardiovascular diseases such as Chronic Obstructive Pulmonary Disease (COPD). Long non-coding RNAs (lncRNAs) have emerged as key modulators of SMC differentiation and phenotypic changes. In this study, we examined the expression of lncRNAs in primary human pulmonary artery SMCs (hPASMCs) during cell-to-cell contact-induced SMC differentiation. We discovered a novel lncRNA, which we named Differentiation And Growth Arrest-Related lncRNA (DAGAR) that was significantly upregulated in the quiescent phenotype with respect to proliferative SMCs and in cell-cycle-arrested MRC5 lung fibroblasts. We demonstrated that DAGAR expression is essential for SMC quiescence and its knockdown hinders SMC differentiation. The treatment of quiescent SMCs with the pro-inflammatory cytokine Tumor Necrosis Factor (TNF), a known inducer of SMC dedifferentiation and proliferation, elicited DAGAR downregulation. Consistent with this, we observed diminished DAGAR expression in pulmonary arteries from COPD patients compared to non-smoker controls. Through pulldown experiments followed by mass spectrometry analysis, we identified several proteins that interact with DAGAR that are related to cell differentiation, the cell cycle, cytoskeleton organization, iron metabolism, and the N-6-Methyladenosine (m6A) machinery. In conclusion, our findings highlight DAGAR as a novel lncRNA that plays a crucial role in the regulation of cell proliferation and SMC differentiation. This paper underscores the potential significance of DAGAR in SMC and fibroblast physiology in health and disease.<\/jats:p>","DOI":"10.3390\/ijms25179497","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T12:22:33Z","timestamp":1725366153000},"page":"9497","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Differentiation and Growth-Arrest-Related lncRNA (DAGAR): Initial Characterization in Human Smooth Muscle and Fibroblast Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6800-6634","authenticated-orcid":false,"given":"Benjamin","family":"de la Cruz-Thea","sequence":"first","affiliation":[{"name":"Mercedes and Martin Ferreyra Medical Research Institute, National Council for Scientific and Technical Research, National University of C\u00f3rdoba (INIMEC-CONICET-UNC), C\u00f3rdoba 5016, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9928-1748","authenticated-orcid":false,"given":"Lautaro","family":"Natali","sequence":"additional","affiliation":[{"name":"Mercedes and Martin Ferreyra Medical Research Institute, National Council for Scientific and Technical Research, National University of C\u00f3rdoba (INIMEC-CONICET-UNC), C\u00f3rdoba 5016, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-1559","authenticated-orcid":false,"given":"Hung","family":"Ho-Xuan","sequence":"additional","affiliation":[{"name":"Regensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"Bruckmann","sequence":"additional","affiliation":[{"name":"Regensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N\u00faria","family":"Coll-Bonfill","sequence":"additional","affiliation":[{"name":"Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-1099","authenticated-orcid":false,"given":"Nicholas","family":"Strieder","sequence":"additional","affiliation":[{"name":"NGS-Core, LIT\u2014Leibniz-Institute for Immunotherapy, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9793-9433","authenticated-orcid":false,"given":"V\u00edctor I.","family":"Peinado","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"},{"name":"Department of Pulmonary Medicine, Hospital Cl\u00ednic, Biomedical Research Institut August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain"},{"name":"Biomedical Research Networking Center in Respiratory Diseases (CIBERES), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunter","family":"Meister","sequence":"additional","affiliation":[{"name":"Regensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melina M.","family":"Musri","sequence":"additional","affiliation":[{"name":"Mercedes and Martin Ferreyra Medical Research Institute, National Council for Scientific and Technical Research, National University of C\u00f3rdoba (INIMEC-CONICET-UNC), C\u00f3rdoba 5016, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,31]]},"reference":[{"key":"ref_1","unstructured":"WHO (2024, August 01). 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