{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:04:31Z","timestamp":1791198271049,"version":"4.1.0"},"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":[[2013,3]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>\n              Acquired heart diseases, such as valve disease, are major causes of human morbidity and mortality. However, the pathological mechanisms underlying these diseases are largely unknown. Our aim is to identify the role of the\n              <jats:italic>hairy and enhancer of split-related<\/jats:italic>\n              (\n              <jats:italic>Hesr<\/jats:italic>\n              )-2 gene in the adult heart.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Echocardiography detected heart dysfunctions indicative of aortic valve anomalies, stenosis, and regurgitation, in \u224859% of &gt;12-month-old\n              <jats:italic>Hesr2<\/jats:italic>\n              knockout survivor mice. Morphological and histological analyses revealed thickened semilunar valves with increased fibrotic areas, indicating that sclerotic degeneration of valves is the main cause of aortic valve disease. The expression of osteogenic genes, such as\n              <jats:italic>Osteopontin<\/jats:italic>\n              and\n              <jats:italic>Sclerostin<\/jats:italic>\n              , were upregulated in the mutants, and the overexpression of\n              <jats:italic>Sclerostin<\/jats:italic>\n              in endothelial cells resulted in thickened semilunar valves with increased fibrotic areas, similar to that seen in the\n              <jats:italic>Hesr2<\/jats:italic>\n              knockout mice, suggesting that\n              <jats:italic>Hesr2<\/jats:italic>\n              can regulate osteogenic gene expression in valves. Reduced left ventricular function, which may be caused by increased ventricular interstitial fibrosis, and enlarged myocardial cell size without ventricular wall thickening were found in both aortic valve stenosis\/regurgitation-positive (33%) and aortic valve stenosis\/regurgitation-negative (38%) subpopulations in 12-month-old survivor mice. Dilated left ventricular internal dimensions were specifically detected in the aortic valve stenosis\/regurgitation-positive subpopulation, thus suggesting that the degeneration of cardiomyocytes is influenced by irregular hemodynamics.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion\u2014<\/jats:title>\n            <jats:p>\n              These data revealed that survivor mice lacking the\n              <jats:italic>Hesr2<\/jats:italic>\n              gene exhibit fibrosis in the aortic valve and ventricle in adulthood, thus suggesting that\n              <jats:italic>Hesr2<\/jats:italic>\n              plays an important role in maintaining the homeostasis of the aortic valve and ventricle.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.112.300573","type":"journal-article","created":{"date-parts":[[2013,1,4]],"date-time":"2013-01-04T06:57:33Z","timestamp":1357282653000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["<i>Hesr2<\/i>\n            Knockout Mice Develop Aortic Valve Disease With Advancing Age"],"prefix":"10.1161","volume":"33","author":[{"given":"Hiroki","family":"Kokubo","sequence":"first","affiliation":[{"name":"From the Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan (H.K., Y.S.); Department of Genetics, The Graduate University for Advanced Studies, Shizuoka, Japan (H.K., Y.S.); Department of Pediatric Cardiology, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T., Y.N., T.N.); Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T.); Feinberg Cardiovascular Research Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Miyagawa-Tomita","sequence":"additional","affiliation":[{"name":"From the Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan (H.K., Y.S.); Department of Genetics, The Graduate University for Advanced Studies, Shizuoka, Japan (H.K., Y.S.); Department of Pediatric Cardiology, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T., Y.N., T.N.); Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T.); Feinberg Cardiovascular Research Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasumi","family":"Nakashima","sequence":"additional","affiliation":[{"name":"From the Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan (H.K., Y.S.); Department of Genetics, The Graduate University for Advanced Studies, Shizuoka, Japan (H.K., Y.S.); Department of Pediatric Cardiology, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T., Y.N., T.N.); Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T.); Feinberg Cardiovascular Research Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Kume","sequence":"additional","affiliation":[{"name":"From the Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan (H.K., Y.S.); Department of Genetics, The Graduate University for Advanced Studies, Shizuoka, Japan (H.K., Y.S.); Department of Pediatric Cardiology, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T., Y.N., T.N.); Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T.); Feinberg Cardiovascular Research Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Yoshizumi","sequence":"additional","affiliation":[{"name":"From the Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan (H.K., Y.S.); Department of Genetics, The Graduate University for Advanced Studies, Shizuoka, Japan (H.K., Y.S.); Department of Pediatric Cardiology, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T., Y.N., T.N.); Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T.); Feinberg Cardiovascular Research Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"From the Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan (H.K., Y.S.); Department of Genetics, The Graduate University for Advanced Studies, Shizuoka, Japan (H.K., Y.S.); Department of Pediatric Cardiology, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T., Y.N., T.N.); Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T.); Feinberg Cardiovascular Research Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Saga","sequence":"additional","affiliation":[{"name":"From the Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan (H.K., Y.S.); Department of Genetics, The Graduate University for Advanced Studies, Shizuoka, Japan (H.K., Y.S.); Department of Pediatric Cardiology, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T., Y.N., T.N.); Division of Cardiovascular Development and Differentiation, Medical Research Institute, Tokyo Women\u2019s Medical University, Tokyo, Japan (S.M.-T.); Feinberg Cardiovascular Research Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.echo.2007.05.006"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1076-7460.2007.07641.x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2007.07.002"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2004.040337"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.191259"},{"key":"e_1_3_4_7_2","volume-title":"Braunwald\u2019s Heart Disease: A Textbook of Cardiovascular Medicine","author":"Otto CM","year":"2008","unstructured":"Otto CM, Bonow RO. Braunwald\u2019s Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: Elsevier Saunders; 2008.","edition":"8"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(96)00563-3"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-003-0456-5"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000227513.13697.ac"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.110.234146"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60252-X"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10208"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg778"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.05.150"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2008.11.008"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.17.6071-6079.2001"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.17.6080-6089.2001"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.09.006"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000141136.85194.f0"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)01149-1"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)01150-8"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.252648999"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702447104"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000261693.13269.bf"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03940"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.05.046"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2007.02.041"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.08.008"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.111.227561"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000070591.21548.69"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22549"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr015"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.110.221358"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiomech.2010.08.026"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehm263"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000260181.19449.95"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.654913"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.109.892224"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00866.2008"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00078.2009"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000055739.13639.d7"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2003.11.058"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.276304"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02344"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.10.025"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.291004"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-011-1162-y"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002401"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.174287"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1338705"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30534"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9390"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.112.300573","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:09:43Z","timestamp":1715555383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.112.300573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3]]},"references-count":52,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2013,3]]}},"alternative-id":["10.1161\/ATVBAHA.112.300573"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.112.300573","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,3]]},"assertion":[{"value":"2012-06-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-11-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-01-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}