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方面都具有重要作用，但它们在心脏中的相互作用仍鲜有研究。在这里，我们提供了心脏细胞中 ErbB2 和 Notch1 之间串扰的证据，对自噬和增殖有影响。 H9c2 成肌细胞中 ErbB2 的过度表达以转录后、p38 依赖性方式诱导 Notch1 激活，而用特异性抑制剂拉帕替尼抑制 ErbB2 可减少 Notch1 激活。此外，将 H9c2 细胞与拉帕替尼一起孵育会导致自噬流停滞并减少增殖，这与该药物和其他 ErbB2 靶向药物已确定的心脏毒性一致。证实了 H9c2 细胞中的发现，将原代新生小鼠心肌细胞暴露于外源性神经调节蛋白-1（它与 ErbB2 结合）刺激了增殖，并且通过同时抑制负责 Notch1 激活的酶来消除这种效应。此外，在心肌细胞中特异性过度表达 ErbB2 的转基因小鼠的心脏中活性 Notch1 和 Notch 相关基因的水平增加。这些数据扩展了对 ErbB2 和 Notch1 在心脏中功能的认识，并可能有助于更好地了解 ErbB2 靶向癌症治疗的心脏毒性机制。© 2024 国际生物化学和分子生物学联盟。

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.© 2024 International Union of Biochemistry and Molecular Biology.