Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin. Issue 24 (13th December 2016)

• Record Type: Journal Article
• Authors: Wo, Da; Peng, Jinhui; Ren, Dan-ni; Qiu, Liman; Chen, Jinxiao; Zhu, Ye; Yan, Yingjing; Yan, Hongwei; Wu, Jian; Ma, En; Zhong, Tao P.; Chen, Yihan; Liu, Zhongmin; Liu, Shangfeng; Ao, Luoquan; Liu, Zhenping; Jiang, Cizhong; Peng, Jun; Zou, Yunzeng; Qian, Qirong; Zhu, Weidong
• Is Part Of: Circulation. Volume 134:Issue 24(2016)
• Publication Date: 2016-12-13
• Subjects: beta-catenin -- Dkk1 protein, mouse -- insulin-like growth factor binding protein 4 -- ischemia -- low-density lipoprotein receptor-related proteins 5 and 6 -- myocardial infarction; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.116.024441
• Languages: English
• ISSNs: 0009-7322

Abstract

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. Abstract : Supplemental Digital Content is available in the text.