Activation of endothelial β-catenin signaling induces heart failure.
Activation of endothelial β-catenin signaling induces heart failure.
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DOI：
10.1038/srep25009
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发表时间：
2016-05-05
影响因子：
4.6
通讯作者：
Komuro I
中科院分区：
文献类型：
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作者：
Nakagawa A;Naito AT;Sumida T;Nomura S;Shibamoto M;Higo T;Okada K;Sakai T;Hashimoto A;Kuramoto Y;Oka T;Lee JK;Harada M;Ueda K;Shiojima I;Limbourg FP;Adams RH;Noda T;Sakata Y;Akazawa H;Komuro I
内皮细胞中β-catenin依赖的典型Wnt信号的激活在发育和缺血性疾病期间的血管生成中起着关键作用，然而，内皮细胞中Wnt/β-catenin信号的其他作用仍然知之甚少。在这里，我们报道内皮细胞中β-catenin信号的持续激活通过抑制心脏中的神经调节蛋白erbb通路导致心功能障碍。在Bmx阳性动脉内皮细胞（Bmx/CA小鼠）中，β-catenin的条件性功能获得突变激活Wnt/β-catenin信号传导，导致他莫昔芬治疗40周后进行性心功能障碍和100%死亡率。电镜分析显示Bmx/CA小鼠心肌细胞t小管扩张和线粒体变性，这与神经调节蛋白erbb信号减少小鼠的变化相似。在Bmx/CA小鼠中，Nrg1和心脏ErbB信号的内皮表达受到抑制。重组神经调节蛋白可改善Bmx/CA小鼠心功能障碍。这些结果共同提示内皮细胞中Wnt/β-catenin信号的持续激活可能是通过抑制神经调节蛋白erbb信号传导导致心力衰竭的原因，并且心脏内皮细胞中的Wnt/β-catenin/NRG轴可能成为心力衰竭的治疗靶点。
Activation of β-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/β-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of β-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of β-catenin, which activates Wnt/β-catenin signaling in Bmx-positive arterial endothelial cells (Bmx/CA mice) led to progressive cardiac dysfunction and 100% mortality at 40 weeks after tamoxifen treatment. Electron microscopic analysis revealed dilatation of T-tubules and degeneration of mitochondria in cardiomyocytes of Bmx/CA mice, which are similar to the changes observed in mice with decreased neuregulin-ErbB signaling. Endothelial expression of Nrg1 and cardiac ErbB signaling were suppressed in Bmx/CA mice. The cardiac dysfunction of Bmx/CA mice was ameliorated by administration of recombinant neuregulin protein. These results collectively suggest that sustained activation of Wnt/β-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/β-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure.