Functional analysis of ErbB receptor signaling in the hearts

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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