{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:13:01Z","timestamp":1789665181377,"version":"4.0.1"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Marfan syndrome (MFS) is an inherited disorder caused by mutations in the\n                      <jats:italic>FBN1<\/jats:italic>\n                      gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      To elucidate the role of endothelial XOR (xanthine oxidoreductase)\u2013derived reactive oxygen species in aortic aneurysm progression, we inhibited in vivo function of XOR either by endothelial cell (EC)\u2013specific disruption of the\n                      <jats:italic>Xdh<\/jats:italic>\n                      gene or by systemic administration of an XOR inhibitor febuxostat in MFS mice harboring the\n                      <jats:italic>Fbn1<\/jats:italic>\n                      missense mutation p.(Cys1041Gly). We assessed the aberrant activation of mechanosensitive signaling in the ascending aorta of\n                      <jats:italic>Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice. Further analysis of human aortic ECs investigated the mechanisms by which mechanical stress upregulates XOR expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We found a significant increase in reactive oxygen species generation in the ascending aorta of patients with MFS and\n                      <jats:italic>Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice, which was associated with a significant increase in protein expression and enzymatic activity of XOR protein in aortic ECs. Genetic disruption of\n                      <jats:italic>Xdh<\/jats:italic>\n                      in ECs or treatment with febuxostat significantly suppressed aortic aneurysm progression and improved perivascular infiltration of macrophages. Mechanistically, mechanosensitive signaling involving FAK (focal adhesion kinase)\u2013p38 MAPK (p38 mitogen-activated protein kinase) and Egr-1 (early growth response-1) was aberrantly activated in the ascending aorta of\n                      <jats:italic>Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice, and mechanical stress on human aortic ECs upregulated XOR expression through Egr-1 upregulation. Consistently, EC-specific knockout of XOR or systemic administration of febuxostat in\n                      <jats:italic>Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice suppressed reactive oxygen species generation, FAK\u2013p38 MAPK activation, and Egr-1 upregulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Aberrant activation of mechanosensitive signaling in vascular ECs triggered endothelial XOR activation and reactive oxygen species generation, which contributes to the progression of aortic aneurysms in MFS. These findings highlight a drug repositioning approach using a uric acid\u2013lowering drug febuxostat as a potential therapy for MFS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.124.321527","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T05:00:27Z","timestamp":1738213227000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["XOR-Derived ROS in Tie2-Lineage Cells Including Endothelial Cells Promotes Aortic Aneurysm Progression in Marfan Syndrome"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6615-6196","authenticated-orcid":true,"given":"Hiroki","family":"Yagi","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."},{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. Yamauchi)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3574-9607","authenticated-orcid":true,"given":"Hiroshi","family":"Akazawa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9021-7665","authenticated-orcid":true,"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimiko","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Laboratory of System Physiology, Department of Biomedical Engineering, Graduate School of Medicine (K.Y.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7739-8545","authenticated-orcid":true,"given":"Kan","family":"Nawata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, St. Marianna University School of Medicine, Kawasaki, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Saga-Kamo","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0331-5617","authenticated-orcid":true,"given":"Masahiko","family":"Umei","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0462-0966","authenticated-orcid":true,"given":"Hiroshi","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8978-7804","authenticated-orcid":true,"given":"Akito","family":"Shindo","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. 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Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-3347","authenticated-orcid":true,"given":"Norifumi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan."},{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. Yamauchi)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Ando","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Graduate School of Medicine (M.A., H. Yamauchi, M.O.), The University of Tokyo, Bunkyo-ku, Japan."},{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. Yamauchi)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1526-1759","authenticated-orcid":true,"given":"Haruo","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Graduate School of Medicine (M.A., H. Yamauchi, M.O.), The University of Tokyo, Bunkyo-ku, Japan."},{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. 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