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Notably, the transforming growth factor (TGF-\u03b2) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-\u03b2 pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.<\/jats:p>","DOI":"10.3390\/ijms24097900","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T02:50:00Z","timestamp":1682563800000},"page":"7900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["SMAD4 Expression in Monocytes as a Potential Biomarker for Atherosclerosis Risk in Patients with Obstructive Sleep Apnea"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4549-0678","authenticated-orcid":false,"given":"Elena","family":"D\u00edaz-Garc\u00eda","sequence":"first","affiliation":[{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain"},{"name":"Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2065-9326","authenticated-orcid":false,"given":"Aldara","family":"Garc\u00eda-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain"},{"name":"Servicio de Neumolog\u00eda, Hospital Universitario Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5228-248X","authenticated-orcid":false,"given":"David","family":"S\u00e1nz-Rubio","sequence":"additional","affiliation":[{"name":"Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-147X","authenticated-orcid":false,"given":"Enrique","family":"Alfaro","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain"},{"name":"Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"L\u00f3pez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Casitas","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain"},{"name":"Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Ma\u00f1as Baena","sequence":"additional","affiliation":[{"name":"Servicio de Neumolog\u00eda, Hospital Universitario Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Cano-Pumarega","sequence":"additional","affiliation":[{"name":"Servicio de Neumolog\u00eda, Hospital Universitario Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Cubero","sequence":"additional","affiliation":[{"name":"Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Marin-Oto","sequence":"additional","affiliation":[{"name":"Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"L\u00f3pez-Collazo","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain"},{"name":"The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9096-2294","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Marin","sequence":"additional","affiliation":[{"name":"Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain"},{"name":"Department of Medicine, University of Zaragoza School of Medicine, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7227-2238","authenticated-orcid":false,"given":"Francisco","family":"Garc\u00eda-R\u00edo","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain"},{"name":"Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain"},{"name":"Faculty of Medicine, Autonomous University of Madrid, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1948-4514","authenticated-orcid":false,"given":"Carolina","family":"Cubillos-Zapata","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain"},{"name":"Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15015","DOI":"10.1038\/nrdp.2015.15","article-title":"Obstructive sleep apnoea syndrome","volume":"1","author":"Levy","year":"2015","journal-title":"Nat. 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