{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T09:59:40Z","timestamp":1793354380159,"version":"4.5.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Hyaluronan (HA) is required for endothelial-to-mesenchymal transition and normal heart development in the mouse. Heart abnormalities in hyaluronidase 2 (HYAL2)\u2013deficient (\n              <jats:italic>Hyal2<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212<\/jats:italic>\n              <\/jats:sup>\n              <jats:sup>\n                <jats:italic>\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              ) mice and humans suggested removal of HA is also important for normal heart development. We have performed longitudinal studies of heart structure and function in\n              <jats:italic>Hyal2<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice to determine when, and how, HYAL2 deficiency leads to these abnormalities.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Echocardiography revealed atrial enlargement, atrial tissue masses, and valvular thickening at 4 weeks of age, as well as diastolic dysfunction that progressed with age, in\n              <jats:italic>Hyal2<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice. These abnormalities were associated with increased HA, vimentin-positive cells, and fibrosis in\n              <jats:italic>Hyal2<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              compared with control mice. Based on the severity of heart dysfunction, acute and chronic groups of\n              <jats:italic>Hyal2<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice that died at an average of 12 and 25 weeks respectively, were defined. Increased HA levels and mesenchymal cells, but not vascular endothelial growth factor in\n              <jats:italic>Hyal2<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              embryonic hearts, suggest that HYAL2 is important to inhibit endothelial-to-mesenchymal transition. Consistent with this, in wild-type embryos, HYAL2 and HA were readily detected, and HA levels decreased with age.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              These data demonstrate that disruption of normal HA catabolism in\n              <jats:italic>Hyal2<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice causes increased HA, which may promote endothelial-to-mesenchymal transition and proliferation of mesenchymal cells. Excess endothelial-to-mesenchymal transition, resulting in increased mesenchymal cells, is the likely cause of morphological heart abnormalities in both humans and mice. In mice, these abnormalities result in progressive and severe diastolic dysfunction, culminating in heart failure.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.116.001598","type":"journal-article","created":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T02:00:24Z","timestamp":1487124024000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure"],"prefix":"10.1161","volume":"10","author":[{"given":"Biswajit","family":"Chowdhury","sequence":"first","affiliation":[{"name":"From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children\u2019s Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Xiang","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children\u2019s Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children\u2019s Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Hemming","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children\u2019s Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vernon W.","family":"Dolinsky","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children\u2019s Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Triggs-Raine","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children\u2019s Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.183056"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.91.2.494"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI10272"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2016.02.072"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.393629"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006470"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.063495"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-012110-142145"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000224114.65109.4e"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1998.9001"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000242561.95978.43"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwg112"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.06.125"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.4331\/wjbc.v6.i3.110"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-111997"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-015-1373-8"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1177\/1933719109348923"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6793-9-11"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.02.007"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwn006"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-0436.1993.tb01591.x"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(84)90233-1"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087437"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0810053106"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22458"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2008.07.021"},{"key":"e_1_3_4_29_2","first-page":"135","article-title":"New non-invasive index for combined systolic and diastolic ventricular function.","volume":"26","author":"Tei C.","year":"1995","unstructured":"Tei C. 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