Functional analysis of ErbB receptor signaling in the hearts

ErbB受体酪氨酸激酶家族由表皮生长因子受体（EGFR）、ErbB 2、ErbB 3和ErbB 4组成，在细胞代谢、存活、增殖和分化等多种细胞反应中发挥重要作用。在脊椎动物中，ErbB受体结合多种EGF相关配体的同源和异源二聚体的组合，从而提供了一个复杂的信号多样性。然而，ErbB受体在出生后心脏中的作用仍有待完全确定。为了阐明ErbB受体在心脏中的作用，我们产生了在α-肌球蛋白重链启动子控制下过表达EGFR显性阴性突变体的转基因小鼠（EGFR-DN小鼠）。静脉注射重组EGF或肝素结合EGF样生长因子诱导野生型心脏中EGFR、ErbB 2和ErbB 4的快速自磷酸化，而EGFR-DN心脏中这些受体的自磷酸化被成功抑制。同时 ...更多信息 EGF诱导的细胞外信号调节激酶1/2和c-Jun N-末端激酶的激活在EGFR-DN心脏中被消除。大多数EGFR-DN小鼠在断奶后自发表现出明显的心力衰竭，并在5 - 20周龄时死亡。超声心动图检查显示EGFR-DN小鼠左室功能不全，室腔扩张，室壁变薄。电镜观察显示EGFR-DN小鼠心肌细胞线粒体超微结构改变，表现为电子密度降低和嵴组织化程度降低。此外，我们发现在EGFR-DN小鼠中更频繁地观察到TUNEL阳性心肌细胞，并且抗凋亡分子如Bcl 2和BclxL的表达减少。因此，通过EGFR同源二聚体和EGFR/ErbB 2、EGF/ErbB 4或ErbB 2/ErbB 4异源二聚体介导的ErbB信号传导对于维持线粒体完整性和功能以及预防心肌细胞凋亡至关重要。这些数据提供了新的见解的意义ErbB信号在心脏内稳态，和ErbB信号通路的组件将被提出作为有前途的治疗靶点，用于治疗心力衰竭。少

ErbB family of receptor tyrosine kinases, consisting of epidermal growth factor receptor (EGFR), ErbB2, ErbB3 and ErbB4, play important roles in a variety of cellular responses including cell metabolism and survivals as well as cell proliferation and differentiation. In vertebrates, ErbB receptors bind to multiple EGF-related ligands with homo- and heterodimer combinations, and thereby provide a complicated signaling diversity. However, the role of ErbB receptors in postnatal hearts remains to be fully determined. To elucidate the role of ErbB receptors in the heart, we generated transgenic mice overexpressing a dominant-negative mutant of EGFR under the control of α-myosin heavy chain promoter (EGFR-DN mice). Intravenous administration of either recombinant EGF or heparin-binding EGF-like growth factor induced rapid autophosphorylation of EGFR, ErbB2, and ErbB4 in wild-type hearts, whereas autophosphorylation of these receptors in EGFR-DN hearts was successfully inhibited. Simultaneou … More sly, EGF-induced activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase was abrogated in EGFR-DN hearts. Most of EGFR-DN mice exhibited overt heart failure spontaneously after weaning and died at 5 - 20 weeks of age. Echogardiographic examination revealed left ventricular dysfunction together with chamber dilatation and wall thinning in EGFR-DN mice. By electron microscopy, cardiomyocytes in EGFR-DN mice showed ultrastructural alterations of mitochondria characteristic of decreased electron density and less-organized cristae. In addition, we found that TUNEL-positive cardiomyocytes were more frequently observed in EGFR-DN mice, and that the expressions of anti-apoptotic molecules such as Bcl2 and BclxL were reduced. Therefore, the ErbB signaling mediated via EGFR homodimer and EGFR/ErbB2, EGF/ErbB4 or ErbB2/ErbB4 heterodimers is essential for maintenance of mitochondrial integrity and function and prevention of cardiomyocyte apoptosis. These data provide new insights into the significance of the ErbB signaling in cardiac homeostasis, and the components of the ErbB signaling pathways will be proposed as promising therapeutic targets for treatment of heart failure. Less