{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:04:54Z","timestamp":1789524294793,"version":"build-2803163510"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,5,4]],"date-time":"2024-05-04T00:00:00Z","timestamp":1714780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Holland\u2013Stichting LSH-TKI","award":["LSHM22018"],"award-info":[{"award-number":["LSHM22018"]}]},{"name":"Health Holland\u2013Stichting LSH-TKI","award":["11I2423N"],"award-info":[{"award-number":["11I2423N"]}]},{"name":"Health Holland\u2013Stichting LSH-TKI","award":["11J3123N"],"award-info":[{"award-number":["11J3123N"]}]},{"name":"Health Holland\u2013Stichting LSH-TKI","award":["12AO124N"],"award-info":[{"award-number":["12AO124N"]}]},{"name":"Health Holland\u2013Stichting LSH-TKI","award":["12X5422N"],"award-info":[{"award-number":["12X5422N"]}]},{"name":"Health Holland\u2013Stichting LSH-TKI","award":["ERC-COG-2017-771945"],"award-info":[{"award-number":["ERC-COG-2017-771945"]}]},{"name":"Health Holland\u2013Stichting LSH-TKI","award":["769036"],"award-info":[{"award-number":["769036"]}]},{"name":"FWO","award":["LSHM22018"],"award-info":[{"award-number":["LSHM22018"]}]},{"name":"FWO","award":["11I2423N"],"award-info":[{"award-number":["11I2423N"]}]},{"name":"FWO","award":["11J3123N"],"award-info":[{"award-number":["11J3123N"]}]},{"name":"FWO","award":["12AO124N"],"award-info":[{"award-number":["12AO124N"]}]},{"name":"FWO","award":["12X5422N"],"award-info":[{"award-number":["12X5422N"]}]},{"name":"FWO","award":["ERC-COG-2017-771945"],"award-info":[{"award-number":["ERC-COG-2017-771945"]}]},{"name":"FWO","award":["769036"],"award-info":[{"award-number":["769036"]}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["LSHM22018"],"award-info":[{"award-number":["LSHM22018"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["11I2423N"],"award-info":[{"award-number":["11I2423N"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["11J3123N"],"award-info":[{"award-number":["11J3123N"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["12AO124N"],"award-info":[{"award-number":["12AO124N"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["12X5422N"],"award-info":[{"award-number":["12X5422N"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC-COG-2017-771945"],"award-info":[{"award-number":["ERC-COG-2017-771945"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["769036"],"award-info":[{"award-number":["769036"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union Third Health Programme","award":["LSHM22018"],"award-info":[{"award-number":["LSHM22018"]}]},{"name":"European Union Third Health Programme","award":["11I2423N"],"award-info":[{"award-number":["11I2423N"]}]},{"name":"European Union Third Health Programme","award":["11J3123N"],"award-info":[{"award-number":["11J3123N"]}]},{"name":"European Union Third Health Programme","award":["12AO124N"],"award-info":[{"award-number":["12AO124N"]}]},{"name":"European Union Third Health Programme","award":["12X5422N"],"award-info":[{"award-number":["12X5422N"]}]},{"name":"European Union Third Health Programme","award":["ERC-COG-2017-771945"],"award-info":[{"award-number":["ERC-COG-2017-771945"]}]},{"name":"European Union Third Health Programme","award":["769036"],"award-info":[{"award-number":["769036"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and \u03b2-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of \u03b2-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg\/kg\/day and 5 mg\/kg\/day) with barbadin, a \u03b2-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg\/kg\/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 \u00b1 0.12 vs. 1.96 \u00b1 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg\/kg\/day), and DMX-200 (90 mg\/kg\/day) with a low dose of losartan (5 mg\/kg\/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G\/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.<\/jats:p>","DOI":"10.3390\/ijms25095025","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T15:05:01Z","timestamp":1715007901000},"page":"5025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2723-9957","authenticated-orcid":false,"given":"Irene","family":"Valdivia Callejon","sequence":"first","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Buccioli","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarl","family":"Bastianen","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Schippers","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Verstraeten","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9668-0535","authenticated-orcid":false,"given":"Ilse","family":"Luyckx","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"},{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-6429","authenticated-orcid":false,"given":"Silke","family":"Peeters","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-3585","authenticated-orcid":false,"given":"A. H. Jan","family":"Danser","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland R. J.","family":"Van Kimmenade","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8516-5856","authenticated-orcid":false,"given":"Josephina","family":"Meester","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3703-9518","authenticated-orcid":false,"given":"Bart","family":"Loeys","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Antwerp, Belgium"},{"name":"Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/352337a0","article-title":"Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene","volume":"352","author":"Dietz","year":"1991","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1136\/jmedgenet-2016-103996","article-title":"Homozygous and compound heterozygous mutations in the FBN1 gene: Unexpected findings in molecular diagnosis of Marfan syndrome","volume":"54","author":"Arnaud","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"582","DOI":"10.21037\/acs.2017.11.03","article-title":"Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome","volume":"6","author":"Meester","year":"2017","journal-title":"Ann. Cardiothorac. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1126\/science.1192152","article-title":"Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism","volume":"332","author":"Habashi","year":"2011","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1161\/ATVBAHA.114.304412","article-title":"Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome","volume":"35","author":"Meirelles","year":"2015","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.gene.2016.07.033","article-title":"FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders","volume":"591","author":"Sakai","year":"2016","journal-title":"Gene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1093\/eurheartj\/ehac823","article-title":"Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection","volume":"44","author":"Yang","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"R13","DOI":"10.1530\/VB-19-0027","article-title":"The genetics and biomechanics of thoracic aortic diseases","volume":"1","author":"Harky","year":"2019","journal-title":"Vasc. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.ijcard.2005.11.116","article-title":"The effect of beta-blocker therapy on clinical outcome in patients with Marfan\u2019s syndrome: A meta-analysis","volume":"114","author":"Gersony","year":"2007","journal-title":"Int. J. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/S0140-6736(22)01534-3","article-title":"Angiotensin receptor blockers and \u03b2 blockers in Marfan syndrome: An individual patient data meta-analysis of randomised trials","volume":"400","author":"Pitcher","year":"2022","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.2337\/diacare.25.6.1072","article-title":"Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate: Effects of angiotensin receptor blockade and sodium restriction","volume":"25","author":"Houlihan","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1126\/science.1124287","article-title":"Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome","volume":"312","author":"Habashi","year":"2006","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1093\/eurheartj\/eht334","article-title":"Losartan reduces aortic dilatation rate in adults with Marfan syndrome: A randomized controlled trial","volume":"34","author":"Groenink","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1056\/NEJMoa0706585","article-title":"Angiotensin II blockade and aortic-root dilation in Marfan\u2019s syndrome","volume":"358","author":"Brooke","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.jacbts.2021.09.006","article-title":"\u03b2-Arrestin-Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension","volume":"6","author":"Ma","year":"2021","journal-title":"JACC Basic. Transl. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.3389\/fphar.2018.01369","article-title":"\u03b2-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders","volume":"9","author":"Hendrickx","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1124\/jpet.110.173005","article-title":"Selectively engaging \u03b2-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance","volume":"335","author":"Violin","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1161\/CIRCHEARTFAILURE.111.962571","article-title":"Cardiorenal actions of TRV120027, a novel \u00df-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: A novel therapeutic strategy for acute heart failure","volume":"4","author":"Boerrigter","year":"2011","journal-title":"Circ. Heart Fail."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1161\/HYPERTENSIONAHA.122.19232","article-title":"Distinct Mechanisms of \u03b2-Arrestin-Biased Agonist and Blocker of AT1R in Preventing Aortic Aneurysm and Associated Mortality","volume":"80","author":"Jara","year":"2023","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/jcph.111","article-title":"First clinical experience with TRV027: Pharmacokinetics and pharmacodynamics in healthy volunteers","volume":"53","author":"Soergel","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"H1516","DOI":"10.1152\/ajpheart.00291.2015","article-title":"The role of \u03b2-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome","volume":"309","author":"Wisler","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1161\/CIRCRESAHA.112.280399","article-title":"\u03b2-Arrestin-2 deficiency attenuates abdominal aortic aneurysm formation in mice","volume":"112","author":"Trivedi","year":"2013","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41421-021-00362-2","article-title":"Single-cell RNA sequencing identifies an Il1rn(+)\/Trem1(+) macrophage subpopulation as a cellular target for mitigating the progression of thoracic aortic aneurysm and dissection","volume":"8","author":"Liu","year":"2022","journal-title":"Cell Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1161\/CIRCULATIONAHA.120.046528","article-title":"Single-Cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns in Control and Aneurysmal Human Aortic Tissue","volume":"142","author":"Li","year":"2020","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jacbts.2019.10.010","article-title":"Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice","volume":"5","author":"Hirakata","year":"2020","journal-title":"JACC Basic. Transl. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.1172\/JCI38308","article-title":"An adventitial IL-6\/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice","volume":"119","author":"Tieu","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ayoub, M.A., Zhang, Y., Kelly, R.S., See, H.B., Johnstone, E.K.M., McCall, E.A., Williams, J.H., Kelly, D.J., and Pfleger, K.D.G. (2015). Functional interaction between angiotensin II receptor type 1 and chemokine (C-C motif) receptor 2 with implications for chronic kidney disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119803"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1001\/jama.2023.4480","article-title":"Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial","volume":"329","author":"Lawler","year":"2023","journal-title":"Jama"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.ajhg.2021.04.019","article-title":"A human importin-\u03b2-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8","volume":"108","author":"Meester","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5734","DOI":"10.1523\/JNEUROSCI.3210-20.2021","article-title":"Barbadin Potentiates Long-Term Effects of Lorcaserin on POMC Neurons and Weight Loss","volume":"41","author":"He","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_31","unstructured":"Dimerix (2024, March 15). DMX-200 for Focal Segmental Glomerulosclerosis (FSGS). Available online: https:\/\/dimerix.com\/products\/dmx-200-for-focal-segmental-glomerulosclerosis\/."},{"key":"ref_32","unstructured":"ISRCTN Registry (2024, March 15). Efficacy and Safety of DMX-200 in Patients with Focal Segmental Glomerulosclerosis. Available online: https:\/\/www.isrctn.com\/ISRCTN72772236."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/5025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:39:43Z","timestamp":1760107183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/5025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,4]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25095025"],"URL":"https:\/\/doi.org\/10.3390\/ijms25095025","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,4]]}}}