1. Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin.
- Author
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Wo D, Peng J, Ren DN, Qiu L, Chen J, Zhu Y, Yan Y, Yan H, Wu J, Ma E, Zhong TP, Chen Y, Liu Z, Liu S, Ao L, Liu Z, Jiang C, Peng J, Zou Y, Qian Q, and Zhu W
- Subjects
- Animals, DNA Damage drug effects, Disease Models, Animal, Down-Regulation drug effects, Histones metabolism, Hydrogen Peroxide toxicity, Insulin-Like Growth Factor Binding Protein 4 genetics, Insulin-Like Growth Factor Binding Protein 4 therapeutic use, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins therapeutic use, Low Density Lipoprotein Receptor-Related Protein-5 antagonists & inhibitors, Low Density Lipoprotein Receptor-Related Protein-5 genetics, Low Density Lipoprotein Receptor-Related Protein-6 antagonists & inhibitors, Low Density Lipoprotein Receptor-Related Protein-6 genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Ischemia metabolism, Myocardial Ischemia prevention & control, Myocytes, Cardiac cytology, Myocytes, Cardiac metabolism, RNA Interference, RNA, Small Interfering metabolism, Recombinant Proteins biosynthesis, Recombinant Proteins pharmacology, Recombinant Proteins therapeutic use, Wnt Proteins antagonists & inhibitors, Wnt Proteins metabolism, beta Catenin antagonists & inhibitors, beta Catenin genetics, Insulin-Like Growth Factor Binding Protein 4 pharmacology, Intercellular Signaling Peptides and Proteins pharmacology, Low Density Lipoprotein Receptor-Related Protein-5 metabolism, Low Density Lipoprotein Receptor-Related Protein-6 metabolism, Myocardial Ischemia pathology, Wnt Signaling Pathway drug effects, beta Catenin metabolism
- 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., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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