Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin

• DOI: 10.1161/circulationaha.116.024441
• Publication Date: 2016-11-02T01:34:51Z
• Authors: Da Wo; Jinhui Peng; Dan-ni Ren; Liman Qiu; Jinxiao Chen; Ye Zhu; Yingjing Yan; Hongwei Yan; Jian Wu; En Ma; Tao P. Zhong; Yihan Chen; Zhongmin Liu; Shangfeng Liu; Luoquan Ao; Zhenping Liu; Cizhong Jiang; Jun Peng; Yunzeng Zou; Qirong Qian; Weidong Zhu
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Myocardial Ischemia; Down-Regulation; Hydrogen Peroxide; Recombinant Proteins; 3. Good health; Histones; Mice, Inbred C57BL; Wnt Proteins; Disease Models, Animal; Mice; 03 medical and health sciences; Low Density Lipoprotein Receptor-Related Protein-5; Insulin-Like Growth Factor Binding Protein 4; Low Density Lipoprotein Receptor-Related Protein-6; Animals; Intercellular Signaling Peptides and Proteins; Myocytes, Cardiac; RNA Interference; RNA, Small Interfering; DNA Damage

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.