{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T03:33:34Z","timestamp":1773286414425,"version":"3.50.1"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2008,10,21]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation. Despite its importance, the mechanisms by which the CTC is protected and the cause of its rupture remain unknown. CTC is an avascular tissue. We investigated the molecular mechanisms underlying the avascularity of CTC and the correlation between avascularity and CTC rupture.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            We found that tenomodulin, which is a recently isolated antiangiogenic factor, was expressed abundantly in the elastin-rich subendothelial outer layer of normal rodent, porcine, canine, and human CTC. Conditioned medium from cultured CTC interstitial cells strongly inhibited tube formation and mobilization of endothelial cells; these effects were partially inhibited by small-interfering RNA against tenomodulin. The immunohistochemical analysis was performed on 12 normal and 16 ruptured CTC obtained from the autopsy or surgical specimen. Interestingly, tenomodulin was locally absent in the ruptured areas of CTC, where abnormal vessel formation, strong expression of vascular endothelial growth factor-A and matrix metalloproteinases, and infiltration of inflammatory cells were observed, but not in the normal or nonruptured area. In anesthetized open-chest dogs, the tenomodulin layer of tricuspid CTC was surgically filed, and immunohistological analysis was performed after several months. This intervention gradually caused angiogenesis and expression of vascular endothelial growth factor-A and matrix metalloproteinases in the core collagen layer in a time-dependent manner.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            These findings provide evidence that tenomodulin is expressed universally in normal CTC in a concentric pattern and that local absence of tenomodulin, angiogenesis, and matrix metalloproteinase activation are associated with CTC rupture.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.108.780031","type":"journal-article","created":{"date-parts":[[2008,10,7]],"date-time":"2008-10-07T00:45:34Z","timestamp":1223340334000},"page":"1737-1747","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Local Tenomodulin Absence, Angiogenesis, and Matrix Metalloproteinase Activation Are Associated With the Rupture of the Chordae Tendineae Cordis"],"prefix":"10.1161","volume":"118","author":[{"given":"Naritaka","family":"Kimura","sequence":"first","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chisa","family":"Shukunami","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daihiko","family":"Hakuno","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatoyo","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigenori","family":"Miura","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denitsa","family":"Docheva","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tokuhiro","family":"Kimura","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasunori","family":"Okada","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goki","family":"Matsumura","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiharu","family":"Shin'oka","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryohei","family":"Yozu","sequence":"additional","affiliation":[{"name":"From the Departments of Regenerative Medicine and Advanced Cardiac Therapeutics (N.K., D.H., M.Y., K.F.), Cardiovascular Surgery (N.K., R.Y.), and Pathology (T.K., Y.O.), Keio University School of Medicine, Tokyo, Japan; 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Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (C.S., S.M., Y.H.); Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinstried, Germany (D.D.); Department of Cardiovascular Surgery, Heart..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-7580.1998.19240573.x"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0046-8177(03)00245-4"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000114565.42679.c6"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.103.11.1522"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.51.32419"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(97)01151-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.2.636-644.2003"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.4245"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1476"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0012-1606(03)00066-6"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20051"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.98.6.1926"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.19.3855"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.03.027"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.21097"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.4271"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.02-0664"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.05.133"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.06.036"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1080\/03008200590935547"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.2.699-705.2005"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01112"},{"key":"e_1_3_2_23_2","first-page":"1193","volume":"42","year":"2001","unstructured":"Funaki H, Sawaguchi S, Yaoeda K, Koyama Y, Yaoita E, Funaki S, Shirakashi M, Oshima Y, Shukunami C, Hiraki Y, Abe H, Yamamoto T. 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