{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:58:55Z","timestamp":1791331135900,"version":"4.3.1"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Vascular aneurysm is an abnormal local dilatation of an artery that can lead to vessel rupture and sudden death. The only treatment involves surgical or endovascular repair or exclusion. There is currently no approved medical therapy for this condition. Recent data established a strong association between genetic variants in the 9p21 chromosomal region in humans and the presence of cardiovascular diseases, including aneurysms. However, the mechanisms linking this 9p21 DNA variant to cardiovascular risk are still unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Here, we show that deletion of the orthologous 70-kb noncoding interval on mouse chromosome 4 (chr4\n              <jats:sup>\u039470kb\/\u039470kb<\/jats:sup>\n              mice) is associated with reduced aortic expression of cyclin-dependent kinase inhibitor genes\n              <jats:italic>p19Arf<\/jats:italic>\n              and\n              <jats:italic>p15Inkb<\/jats:italic>\n              . Vascular smooth muscle cells from chr4\n              <jats:sup>\u039470kb\/\u039470kb<\/jats:sup>\n              mice show reduced transforming growth factor-\u03b2\u2013dependent canonical Smad2 signaling but increased cyclin-dependent kinase\u2013dependent Smad2 phosphorylation at linker sites, a phenotype previously associated with tumor growth and consistent with the mechanistic link between reduced canonical transforming growth factor-\u03b2 signaling and susceptibility to vascular diseases. We also show that targeted deletion of the 9p21 risk interval promotes susceptibility to aneurysm development and rupture when mice are subjected to a validated model of aneurysm formation. The vascular disease of chr4\n              <jats:sup>\u039470kb\/\u039470kb<\/jats:sup>\n              mice is prevented by treatment with a cyclin-dependent kinase inhibitor.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>The results establish a direct mechanistic link between 9p21 noncoding risk interval and susceptibility to aneurysm and may have important implications for the understanding and treatment of vascular diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.114.000696","type":"journal-article","created":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:08:11Z","timestamp":1409530091000},"page":"799-805","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Deletion of Chromosome 9p21 Noncoding Cardiovascular Risk Interval in Mice Alters Smad2 Signaling and Promotes Vascular Aneurysm"],"prefix":"10.1161","volume":"7","author":[{"given":"C\u00e9line","family":"Loinard","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Basatemur","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leanne","family":"Masters","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Baker","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Harrison","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nichola","family":"Figg","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Vilar","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Sage","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziad","family":"Mallat","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Universit\u00e9 Paris-Descartes, Paris, France (J.V., Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2010.180"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq337"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.72"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/HCO.0b013e32835f0d55"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.563"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.110.586529"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.109.576694"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08801"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7818"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38136"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.09.017"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000058404.92759.32"},{"key":"e_1_3_3_14_2","first-page":"1143","article-title":"Flavopiridol (L86 8275; 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