Abstract：
Although the epidermal growth factor receptor 2 (ErbB2) and Notch1 signaling pathways have both significant roles in regulating cardiac biology, their interplay in the heart remains poorly investigated. Here, we present evidence of a crosstalk between ErbB2 and Notch1 in cardiac cells, with effects on autophagy and proliferation. Overexpression of ErbB2 in H9c2 cardiomyoblasts induced Notch1 activation in a post-transcriptional, p38-dependent manner, while ErbB2 inhibition with the specific inhibitor, lapatinib, reduced Notch1 activation. Moreover, incubation of H9c2 cells with lapatinib resulted in stalled autophagic flux and decreased proliferation, consistent with the established cardiotoxicity of this and other ErbB2-targeting drugs. Confirming the findings in H9c2 cells, exposure of primary neonatal mouse cardiomyocytes to exogenous neuregulin-1, which engages ErbB2, stimulated proliferation, and this effect was abrogated by concomitant inhibition of the enzyme responsible for Notch1 activation. Furthermore, the hearts of transgenic mice specifically overexpressing ErbB2 in cardiomyocytes had increased levels of active Notch1 and of Notch-related genes. These data expand the knowledge of ErbB2 and Notch1 functions in the heart and may allow better understanding the mechanisms of the cardiotoxicity of ErbB2-targeting cancer treatments.
摘要：
尽管表皮生长因子受体2（ErbB2）和Notch1信号通路在调节心脏生物学中都有重要作用，它们在心脏中的相互作用仍然缺乏研究。这里,我们提供了ErbB2和Notch1在心脏细胞中的串扰的证据，对自噬和增殖有影响。ErbB2在H9c2心肌细胞中的过表达诱导Notch1在转录后激活,P38依赖方式，而ErbB2用特异性抑制剂抑制，拉帕替尼,减少Notch1激活。此外，H9c2细胞与拉帕替尼孵育导致自噬通量停滞和增殖减少，与该药物和其他ErbB2靶向药物的既定心脏毒性一致。证实了在H9c2细胞中的发现，原代新生小鼠心肌细胞暴露于外源性神经调节蛋白-1，参与ErbB2，刺激增殖，并且这种作用通过同时抑制负责Notch1活化的酶而消除。此外，在心肌细胞中特异性过表达ErbB2的转基因小鼠的心脏中,活性Notch1和Notch相关基因的水平升高.这些数据扩展了ErbB2和Notch1在心脏中功能的知识，并可以更好地了解ErbB2靶向癌症治疗的心脏毒性机制。
