Da Wo1, Jinhui Peng1, Dan-Ni Ren1, Liman Qiu1, Jinxiao Chen1, Ye Zhu1, Yingjing Yan1, Hongwei Yan1, Jian Wu1, En Ma1, Tao P Zhong1, Yihan Chen1, Zhongmin Liu1, Shangfeng Liu1, Luoquan Ao1, Zhenping Liu1, Cizhong Jiang1, Jun Peng1, Yunzeng Zou1, Qirong Qian1, Weidong Zhu2. 1. 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 of Signaling and Disease Research, The School of Life Sciences and Technology, Tongji University, China (Zhenping Liu, C.J.); State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Sciences, Fudan University, Shanghai, China (Y.Y., T.Z.); and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (J.W., Y. Zou). 2. 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 of Signaling and Disease Research, The School of Life Sciences and Technology, Tongji University, China (Zhenping Liu, C.J.); State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Sciences, Fudan University, Shanghai, China (Y.Y., T.Z.); and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (J.W., Y. Zou). wzhu@tongji.edu.cn zou.yunzeng@zs-hospital.sh.cn qianqr@163.com.
Abstract
BACKGROUND: 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/β-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/β-catenin pathway activation. However, their roles in the adult heart remain unexplored. METHODS: To understand the role of LRP5/6 and β-catenin in the adult heart, we constructed conditional cardiomyocyte-specific LRP5/6 and β-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 β-catenin. RESULTS: Deletion of LRP5/6 promoted cardiac ischemic insults. Conversely, deficiency of β-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/β-catenin pathway inhibitors, insulin-like growth factor binding protein 4 protected the ischemic heart by inhibiting β-catenin, whereas Dkk1 enhanced the injury response mainly through inducing LRP5/6 endocytosis and degradation. CONCLUSIONS: 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 β-catenin signaling within the Wnt/β-catenin pathway.
BACKGROUND: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/β-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/β-catenin pathway activation. However, their roles in the adult heart remain unexplored. METHODS: To understand the role of LRP5/6 and β-catenin in the adult heart, we constructed conditional cardiomyocyte-specific LRP5/6 and β-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 β-catenin. RESULTS: Deletion of LRP5/6 promoted cardiac ischemic insults. Conversely, deficiency of β-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/β-catenin pathway inhibitors, insulin-like growth factor binding protein 4 protected the ischemic heart by inhibiting β-catenin, whereas Dkk1 enhanced the injury response mainly through inducing LRP5/6 endocytosis and degradation. CONCLUSIONS: 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 β-catenin signaling within the Wnt/β-catenin pathway.
Authors: Sébastien Foulquier; Evangelos P Daskalopoulos; Gentian Lluri; Kevin C M Hermans; Arjun Deb; W Matthijs Blankesteijn Journal: Pharmacol Rev Date: 2018-01 Impact factor: 25.468