Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin
Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin
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通过 LRP5/6 和 β-catenin 的差异靶向作用，Wnt 抑制剂 IGFBP-4 和 Dkk1 在心脏缺血中发挥相反作用
DOI：
10.1161/circulationaha.116.024441
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发表时间：
2016-12-13
期刊：
影响因子：
37.8
通讯作者：
Zhu, Weidong
中科院分区：
文献类型：
--
作者：
Wo, Da;Peng, Jinhui;Zhu, Weidong
背景：心肌梗死是全世界发病和死亡的主要原因之一，引发不可逆的心肌细胞损伤和心力衰竭。低密度脂蛋白受体相关蛋白 5 和 6 (LRP5/6) 作为成人心脏中 Wnt/β-catenin 通路的辅助受体的作用仍不清楚。胰岛素样生长因子结合蛋白 4 和 dickkopf 相关蛋白 1 (Dkk1) 是两种分泌型 LRP5/6 结合蛋白，它们通过阻止 Wnt/β-连环蛋白通路激活在心脏发育中发挥至关重要的作用。然而，它们在成人心脏中的作用仍有待探索。方法：为了了解LRP5/6和β-catenin在成人心脏中的作用，我们构建了条件性心肌细胞特异性LRP5/6和β-catenin基因敲除小鼠并诱导手术心肌梗死。我们还在心肌梗死后立即将胰岛素样生长因子结合蛋白4和Dkk1的重组蛋白直接注射到心脏中，以进一步研究这些蛋白调节LRP5/6和β-连环蛋白的机制。 结果：LRP5/6的缺失促进了心脏缺血性损伤。相反，LRP5/6 下游靶标 β-连环蛋白的缺乏有利于缺血性损伤。有趣的是，尽管胰岛素样生长因子结合蛋白 4 和 Dkk1 都是分泌型 Wnt/β-catenin 通路抑制剂，但胰岛素样生长因子结合蛋白 4 通过抑制 β-catenin 来保护缺血心脏，而 Dkk1 主要通过诱导 LRP5/6 内吞和降解来增强损伤反应。 结论：我们的研究结果揭示 LRP5/6 参与心肌细胞对缺血性损伤的反应，此前未明确其双重作用。这些发现提出了通过微调 Wnt/β-catenin 通路内的 LRP5/6 和 β-catenin 信号传导来治疗缺血性心脏病的新策略。
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.