Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy
Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy
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DOI：
10.1073/pnas.122249299
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发表时间：
2002-06-25
影响因子：
11.1
通讯作者：
Garratt, AN
中科院分区：
文献类型：
--
作者：
Özcelik, C;Erdmann, B;Garratt, AN
ErbB 2（Her 2）原癌基因编码受体酪氨酸激酶，其在人类肿瘤中频繁扩增和过表达。ErbB 2为用于治疗乳腺癌的新型有效的基于抗体的疗法（曲妥珠单抗/赫赛汀）提供了靶点。然而，心肌病的发展与曲妥珠单抗治疗的患者的比例，并通过与标准化疗的组合，这种并发症的发生率增加。基因消融研究已经证实ErbB 2受体及其辅助受体ErbB 4和配体Neuregulin-1对心室的正常发育至关重要。我们使用Cre-loxP技术特异性地在心室心肌细胞中突变ErbB 2。条件突变小鼠发展为严重的扩张型心肌病，通常在出生后第二个月出现心功能不全的迹象。我们推断，来自ErbB 2受体的信号传导对成人心脏功能至关重要，ErbB 2受体在心肌细胞的T-小管中富集。条件性ErbB 2突变小鼠提供了扩张型心肌病模型。特别是，它们将允许严格评估ErbB 2在心脏中的作用，并深入了解抗ErbB 2抗体不良反应的分子机制。
The ErbB2 (Her2) proto-oncogene encodes a receptor tyrosine kinase, which is frequently amplified and overexpressed in human tumors. ErbB2 provides the target for a novel and effective antibody-based therapy (Trastuzumab/Herceptin) used for the treatment of mammary carcinomas. However, cardiomyopathies develop in a proportion of patients treated with Trastuzumab, and the incidence of such complications is increased by combination with standard chemotherapy. Gene ablation studies have previously demonstrated that the ErbB2 receptor, together with its coreceptor ErbB4 and the ligand Neuregulin-1, are essential for normal development of the heart ventricle. We use here Cre-loxP technology to mutate ErbB2 specifically in ventricular cardiomyocytes. Conditional mutant mice develop a severe dilated cardiomyopathy, with signs of cardiac dysfunction generally appearing by the second postnatal month. We infer that signaling from the ErbB2 receptor, which is enriched in T-tubules in cardiomyocytes, is crucial for adult heart function. Conditional ErbB2 mutant mice provide a model of dilated cardiomyopathy. In particular, they will allow a rigorous assessment of the role of ErbB2 in the heart and provide insight into the molecular mechanisms that underlie the adverse effects of anti-ErbB2 antibodies.