{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:00:12Z","timestamp":1777100412329,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T00:00:00Z","timestamp":1640908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["2014T007"],"award-info":[{"award-number":["2014T007"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001828","name":"Erasmus University Rotterdam","doi-asserted-by":"publisher","award":["Fellowship to Ingrid M.B.H. van de Laar"],"award-info":[{"award-number":["Fellowship to Ingrid M.B.H. van de Laar"]}],"id":[{"id":"10.13039\/501100001828","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-\u03b2 gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options.<\/jats:p>","DOI":"10.3390\/ijms23010438","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T20:49:38Z","timestamp":1641242978000},"page":"438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Multi-Omics Profiling in Marfan Syndrome: Further Insights into the Molecular Mechanisms Involved in Aortic Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0340-3433","authenticated-orcid":false,"given":"Judith M. A.","family":"Verhagen","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce","family":"Burger","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Molecular Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos A.","family":"Bekkers","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander T.","family":"den Dekker","sequence":"additional","affiliation":[{"name":"Center for Biomics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9699-4860","authenticated-orcid":false,"given":"Jan H.","family":"von der Th\u00fcsen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Clinical Bioinformatics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Zajec","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Neurology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hennie T.","family":"Br\u00fcggenwirth","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne L. T.","family":"van der Sterre","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myrthe","family":"van den Born","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theo M.","family":"Luider","sequence":"additional","affiliation":[{"name":"Department of Neurology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0421-8301","authenticated-orcid":false,"given":"Wilfred F. J.","family":"van IJcken","sequence":"additional","affiliation":[{"name":"Center for Biomics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marja W.","family":"Wessels","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen","family":"Essers","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Vascular Surgery, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Radiation Oncology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6770-3830","authenticated-orcid":false,"given":"Jolien W.","family":"Roos-Hesselink","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid","family":"van der Pluijm","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Vascular Surgery, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2523-1230","authenticated-orcid":false,"given":"Ingrid M. B. H.","family":"van de Laar","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8235-4010","authenticated-orcid":false,"given":"Erwin","family":"Brosens","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.athoracsur.2006.04.098","article-title":"Familial thoracic aortic aneurysms and dissections\u2014Incidence, modes of inheritance, and phenotypic patterns","volume":"82","author":"Albornoz","year":"2006","journal-title":"Ann. Thorac. 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