{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T20:32:13Z","timestamp":1793046733056,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of North Carolina at Chapel Hill and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health","award":["R01HL169390"],"award-info":[{"award-number":["R01HL169390"]}]},{"name":"University of North Carolina at Chapel Hill and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health","award":["R56HL161454"],"award-info":[{"award-number":["R56HL161454"]}]},{"name":"University of North Carolina at Chapel Hill and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health","award":["R01HL102121"],"award-info":[{"award-number":["R01HL102121"]}]},{"name":"University of North Carolina at Chapel Hill and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health","award":["R21HL148363"],"award-info":[{"award-number":["R21HL148363"]}]},{"name":"University of North Carolina at Chapel Hill and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health","award":["P30 DK034987"],"award-info":[{"award-number":["P30 DK034987"]}]},{"name":"Development of a Liquid Biopsy Based Diagnostic Test for Assessing Thoracic Aortic Aneurysm Disease","award":["R01HL169390"],"award-info":[{"award-number":["R01HL169390"]}]},{"name":"Development of a Liquid Biopsy Based Diagnostic Test for Assessing Thoracic Aortic Aneurysm Disease","award":["R56HL161454"],"award-info":[{"award-number":["R56HL161454"]}]},{"name":"Development of a Liquid Biopsy Based Diagnostic Test for Assessing Thoracic Aortic Aneurysm Disease","award":["R01HL102121"],"award-info":[{"award-number":["R01HL102121"]}]},{"name":"Development of a Liquid Biopsy Based Diagnostic Test for Assessing Thoracic Aortic Aneurysm Disease","award":["R21HL148363"],"award-info":[{"award-number":["R21HL148363"]}]},{"name":"Development of a Liquid Biopsy Based Diagnostic Test for Assessing Thoracic Aortic Aneurysm Disease","award":["P30 DK034987"],"award-info":[{"award-number":["P30 DK034987"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01HL169390"],"award-info":[{"award-number":["R01HL169390"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R56HL161454"],"award-info":[{"award-number":["R56HL161454"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01HL102121"],"award-info":[{"award-number":["R01HL102121"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R21HL148363"],"award-info":[{"award-number":["R21HL148363"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["P30 DK034987"],"award-info":[{"award-number":["P30 DK034987"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave the way they do in other cardiovascular pathologies. EMMPRIN is shed into the circulation through the secretion of extracellular vesicles. This has been demonstrated to be dependent upon the Membrane Type-1 MMP (MT1-MMP). We investigated this relationship in MFS TAA tissue and plasma to discern why unique profiles may exist. Methods: Protein targets were measured in aortic tissue and plasma from MFS patients with TAAs and were compared to healthy controls. The abundance and location of MT1-MMP was modified in aortic fibroblasts and secreted EMMPRIN was measured in conditioned culture media. Results: EMMPRIN levels were elevated in MFS TAA tissue but reduced in plasma, compared to the controls. Tissue EMMPRIN elevation did not induce MMP-3, MMP-8, or TIMP-1 expression, while MT1-MMP and TIMP-2 were elevated. MMP-2 and MMP-9 were reduced in TAA tissue but increased in plasma. In aortic fibroblasts, EMMPRIN secretion required the internalization of MT1-MMP. Conclusions: In MFS, impaired EMMPRIN secretion likely contributes to higher tissue levels, influenced by MT1-MMP cellular localization. Low EMMPRIN levels, in conjunction with other MMP analytes, distinguished MFS TAAs from controls, suggesting diagnostic potential.<\/jats:p>","DOI":"10.3390\/jcm13061548","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T03:52:11Z","timestamp":1709869931000},"page":"1548","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Paradoxical Changes: EMMPRIN Tissue and Plasma Levels in Marfan Syndrome-Related Thoracic Aortic Aneurysms"],"prefix":"10.3390","volume":"13","author":[{"given":"Kyle C.","family":"Alexander","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlton W.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Advanced Analytics Core, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7157-814X","authenticated-orcid":false,"given":"Chris B.","family":"Agala","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Tasoudis","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth N.","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Blackwell","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle E.","family":"Willcox","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behzad S.","family":"Farivar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina R.","family":"Kibbe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Ikonomidis","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8117-0591","authenticated-orcid":false,"given":"Adam W.","family":"Akerman","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.2353\/ajpath.2009.081141","article-title":"Alterations in aortic cellular constituents during thoracic aortic aneurysm development: Myofibroblast-mediated vascular remodeling","volume":"175","author":"Jones","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1080\/07853890310001285","article-title":"Extracellular matrix remodeling following myocardial injury","volume":"35","author":"Lindsey","year":"2003","journal-title":"Ann. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1038\/sj.onc.1207070","article-title":"The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions","volume":"23","author":"Sidhu","year":"2004","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37576","DOI":"10.1074\/jbc.M606993200","article-title":"Membrane type 1 matrix metalloproteinase (MT1-MMP\/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells","volume":"281","author":"Egawa","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.jtcvs.2016.10.065","article-title":"Regulation of membrane type-1 matrix metalloproteinase activity and intracellular localization in clinical thoracic aortic aneurysms","volume":"153","author":"Ikonomidis","year":"2017","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"H114","DOI":"10.1152\/ajpheart.00028.2010","article-title":"Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model","volume":"299","author":"Jones","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Perrucci, G.L., Rurali, E., Corliano, M., Balzo, M., Piccoli, M., Moschetta, D., Pini, A., Gaetano, R., Antona, C., and Egea, G. (2020). Cyclophilin A\/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients. Cells, 9.","DOI":"10.3390\/cells9010154"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.7150\/thno.30714","article-title":"Soluble EMMPRIN levels discriminate aortic ectasia in Marfan syndrome patients","volume":"9","author":"Rurali","year":"2019","journal-title":"Theranostics"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ni, K., Wang, C., Carnino, J.M., and Jin, Y. (2020). The Evolving Role of Caveolin-1: A Critical Regulator of Extracellular Vesicles. Med. Sci., 8.","DOI":"10.3390\/medsci8040046"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2192377","DOI":"10.1080\/19336950.2023.2192377","article-title":"Fibrillin-1 mutation contributes to Marfan syndrome by inhibiting Cav1.2-mediated cell proliferation in vascular smooth muscle cells","volume":"17","author":"Lin","year":"2023","journal-title":"Channels"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Diehl, J.N., Ray, A., Collins, L.B., Peterson, A., Alexander, K.C., Boutros, J.G., Ikonomidis, J.S., and Akerman, A.W. (2023). A standardized method for plasma extracellular vesicle isolation and size distribution analysis. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0284875"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e019862","DOI":"10.1161\/JAHA.120.019862","article-title":"miR-133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice","volume":"10","author":"Akerman","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4782","DOI":"10.1093\/emboj\/20.17.4782","article-title":"Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion","volume":"20","author":"Itoh","year":"2001","journal-title":"EMBO J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chellaiah, M.A., and Ma, T. (2013). Membrane localization of membrane type 1 matrix metalloproteinase by CD44 regulates the activation of pro-matrix metalloproteinase 9 in osteoclasts. Biomed. Res. Int., 2013.","DOI":"10.1155\/2013\/302392"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/cr.1998.18","article-title":"Cell surface activation of progelatinase A (proMMP-2) and cell migration","volume":"8","author":"Nagase","year":"1998","journal-title":"Cell Res."},{"key":"ref_16","first-page":"3154","article-title":"Tumor cell-derived collagenase-stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase","volume":"53","author":"Kataoka","year":"1993","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s10067-012-1949-9","article-title":"Increased serum soluble CD147 levels in patients with systemic sclerosis: Association with scleroderma renal crisis","volume":"31","author":"Yanaba","year":"2012","journal-title":"Clin. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mackay, C.D.A., Jadli, A.S., Fedak, P.W.M., and Patel, V.B. (2022). Adventitial Fibroblasts in Aortic Aneurysm: Unraveling Pathogenic Contributions to Vascular Disease. Diagnostics, 12.","DOI":"10.3390\/diagnostics12040871"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E79","DOI":"10.25011\/cim.v39i3.26796","article-title":"Plasma EMMPRIN levels in acute myocardial infarction and stable coronary artery disease","volume":"39","author":"Akkus","year":"2016","journal-title":"Clin. Invest. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4187","DOI":"10.1111\/febs.13414","article-title":"Soluble extracellular matrix metalloproteinase inducer (EMMPRIN, EMN) regulates cancer-related cellular functions by homotypic interactions with surface CD147","volume":"282","author":"Knutti","year":"2015","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/jgh.13148","article-title":"Circulating CD147 predicts mortality in advanced hepatocellular carcinoma","volume":"31","author":"Lee","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/1479-5876-12-190","article-title":"Full-length soluble CD147 promotes MMP-2 expression and is a potential serological marker in detection of hepatocellular carcinoma","volume":"12","author":"Wu","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kaushik, D.K., Yong, H.Y., Hahn, J.N., Silva, C., Casha, S., Hurlbert, R.J., Jacques, F.H., Lisak, R., Khan, O., and Ionete, C. (2016). Evaluating Soluble EMMPRIN as a Marker of Disease Activity in Multiple Sclerosis: Studies of Serum and Cerebrospinal Fluid. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163802"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S551","DOI":"10.21037\/jtd.2017.03.97","article-title":"Comparing American, European and Asian practice guidelines for aortic diseases","volume":"9","author":"Rozado","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.jacc.2009.08.084","article-title":"Thoracic aortic aneurysm clinically pertinent controversies and uncertainties","volume":"55","author":"Elefteriades","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","first-page":"4823","article-title":"Interstitial collagenases as markers of tumor progression","volume":"6","author":"Brinckerhoff","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1182\/blood-2002-05-1593","article-title":"Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix","volume":"101","author":"Collen","year":"2003","journal-title":"Blood"},{"key":"ref_28","first-page":"1","article-title":"MMPs and TIMPs. An historical perspective","volume":"151","author":"Woessner","year":"2001","journal-title":"Methods Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1161\/CIRCULATIONAHA.104.502617","article-title":"Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis","volume":"111","author":"Stawowy","year":"2005","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.cardiores.2005.09.004","article-title":"Integrins, membrane-type matrix metalloproteinases and ADAMs: Potential implications for cardiac remodeling","volume":"69","author":"Manso","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5331","DOI":"10.1074\/jbc.270.10.5331","article-title":"Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease","volume":"270","author":"Strongin","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26411","DOI":"10.1074\/jbc.M001270200","article-title":"TIMP-2 is required for efficient activation of proMMP-2 in vivo","volume":"275","author":"Wang","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1091\/mbc.e03-07-0516","article-title":"Caveolae are a novel pathway for membrane-type 1 matrix metalloproteinase traffic in human endothelial cells","volume":"15","author":"Galvez","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11112","DOI":"10.1074\/jbc.M312947200","article-title":"Caveolin-1 regulates matrix metalloproteinases-1 induction and CD147\/EMMPRIN cell surface clustering","volume":"279","author":"Tang","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"L1007","DOI":"10.1152\/ajplung.90207.2008","article-title":"The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties","volume":"295","author":"Teeters","year":"2008","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1091\/mbc.e08-08-0830","article-title":"Fibrillin assembly requires fibronectin","volume":"20","author":"Sabatier","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.cardfail.2007.04.010","article-title":"Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs)","volume":"13","author":"Bonnema","year":"2007","journal-title":"J. Card. Fail."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/6\/1548\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:10:43Z","timestamp":1760105443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/6\/1548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,8]]},"references-count":37,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["jcm13061548"],"URL":"https:\/\/doi.org\/10.3390\/jcm13061548","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,8]]}}}