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

Article

关键词: MYOCARDIAL-INFARCTION;    SIGNAL-TRANSDUCTION;    DOWN-REGULATION;    HEART-FAILURE;    DNA-DAMAGE;    LRP6;    RECEPTOR;    ACTIVATION;    PROTEINS;    PATHWAY;   

DOI  :  10.1161/CIRCULATIONAHA.116.024441

来源: SCIE

【 摘 要 】

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/beta-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/beta-catenin pathway activation. However, their roles in the adult heart remain unexplored. METHODS: To understand the role of LRP5/6 and beta-catenin in the adult heart, we constructed conditional cardiomyocyte-specific LRP5/6 and beta-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 beta-catenin. RESULTS: Deletion of LRP5/6 promoted cardiac ischemic insults. Conversely, deficiency of beta-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/beta-catenin pathway inhibitors, insulin-like growth factor binding protein 4 protected the ischemic heart by inhibiting beta-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 beta-catenin signaling within the Wnt/beta-catenin pathway.

【 授权许可】

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