{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:24:56Z","timestamp":1790555096015,"version":"4.1.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2016,12,13]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Myocardial infarction is one of the leading causes of morbidity and mortality worldwide, triggering irreversible myocardial cell damage and heart failure. The role of low-density lipoprotein receptor-related proteins 5 and 6 (LRP5\/6) as coreceptors of the Wnt\/\u03b2-catenin pathway in the adult heart remain unknown. Insulin-like growth factor binding protein 4 and dickkopf-related protein 1 (Dkk1) are 2 secreted LRP5\/6 binding proteins that play a crucial role in heart development through preventing Wnt\/\u03b2-catenin pathway activation. However, their roles in the adult heart remain unexplored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>To understand the role of LRP5\/6 and \u03b2-catenin in the adult heart, we constructed conditional cardiomyocyte-specific LRP5\/6 and \u03b2-catenin knockout mice and induced surgical myocardial infarction. We also directly injected recombinant proteins of insulin-like growth factor binding protein 4 and Dkk1 into the heart immediately following myocardial infarction to further examine the mechanisms through which these proteins regulate LRP5\/6 and \u03b2-catenin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>Deletion of LRP5\/6 promoted cardiac ischemic insults. Conversely, deficiency of \u03b2-catenin, a downstream target of LRP5\/6, was beneficial in ischemic injury. It is interesting to note that although both insulin-like growth factor binding protein 4 and Dkk1 are secreted Wnt\/\u03b2-catenin pathway inhibitors, insulin-like growth factor binding protein 4 protected the ischemic heart by inhibiting \u03b2-catenin, whereas Dkk1 enhanced the injury response mainly through inducing LRP5\/6 endocytosis and degradation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our findings reveal previously unidentified dual roles of LRP5\/6 involved in the cardiomyocyte response to ischemic injury. These findings suggest new therapeutic strategies in ischemic heart disease by fine-tuning LRP5\/6 and \u03b2-catenin signaling within the Wnt\/\u03b2-catenin pathway.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.116.024441","type":"journal-article","created":{"date-parts":[[2016,11,2]],"date-time":"2016-11-02T01:34:51Z","timestamp":1478050491000},"page":"1991-2007","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":96,"title":["Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5\/6 and \u03b2-catenin"],"prefix":"10.1161","volume":"134","author":[{"given":"Da","family":"Wo","sequence":"first","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Peng","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan-ni","family":"Ren","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liman","family":"Qiu","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxiao","family":"Chen","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhu","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjing","family":"Yan","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Yan","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. 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Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao P.","family":"Zhong","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Chen","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongmin","family":"Liu","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangfeng","family":"Liu","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luoquan","family":"Ao","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenping","family":"Liu","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. Zhu, Y.Y., H.Y., E.M., Y.C., Zhongmin Liu, S.L., L.A., W.Z.); Department of Orthopedics, Changzheng Hospital, Shanghai, China (Jinhui Peng, Q.Q.); Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China (L.Q., Jun Peng); Shanghai Key Laboratory..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cizhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"From Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, China (D.W., Jinhui Peng, D.-n.R., J.C., Y. 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