Lopes-Conceição Luisa, Dias-Neto Marina, Fontes-Sousa Ana Patrícia, Mendes-Ferreira Pedro, Maia-Rocha Carolina, Henriques-Coelho Tiago, de Keulenaer Gilles, Leite Moreira Adelino F, Brás-Silva Carmen
Serviço de Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
Acta Med Port. 2011 Dec;24 Suppl 4:1009-20. Epub 2011 Dec 31.
The family of Neuregulins (NRG), growth factors like epidermal growth factor, is known to induce growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells. This family comprises four members, being NRG1 the most largely studied, particularly at the cardiovascular level. The biological effects of NRG1 in the adult heart are mediated by the tyrosine kinase receptors ErbB. In the adult heart, NRG1 is expressed by cells of the endocardial endothelium and the cardiac microvascular endothelium, and the receptors ErbB2/ErbB4 are expressed by ventricular cardiomyocytes and are located in T-tubule system and intercalated disks in close proximity to the system components of excitation-contraction coupling. The importance of the NRG/ErbB signaling axis at the cardiovascular level became evident after discovering that patients treated with trastuzumab (inhibitory antibody against ErbB2, used in the treatment of breast cancer) can develop ventricular dysfunction and have higher risk of cardiomyopathy when co-administered with anthracyclines. Subsequent studies in vitro and in vivo have clarified the effects and the respective signaling pathways associated with the NRG/ErbB system in the adult heart. Some cardiovascular functions of the NRG1/ErbB system have been described at the vascular (stimulation of angiogenesis and ateroprotector effect) and myocardium level (negative inotropic effect) as well as effect on the survival, cell growth and organization of the cardiomyocytes (myofibrillar organization and cell-to-cell contact between cardiomyocytes). Furthermore, the interaction of this system with other neurohumoral mediators has been studied. Thus, there seems to be a physiological role in modulating the sympathovagal balance and an interaction with endothelin-1 signaling. All these effects result from the activation of different intracellular signaling cascades, as a consequence of the binding of NRG1 to ErbB receptors. Some cardiac signaling pathways identified until now include molecules such as MEK / Erk 1/2, phosphatidylinositol 3-kinase/ Akt, focal adhesion kinase, Gab (Grb-2-associated binder) family, vascular endothelial growth factor and NO production by endothelial nitric oxide synthase. Thus, the aim of this paper was to make an up-to-date review of existing information on NRG1/ErbB signaling axis, with particular focus on its cardiovascular effects.
神经调节蛋白（NRG）家族是一类生长因子，类似于表皮生长因子，已知可诱导上皮细胞、神经胶质细胞、神经元细胞和骨骼肌细胞的生长与分化。该家族由四个成员组成，其中NRG1是研究最为广泛的，尤其是在心血管领域。NRG1在成年心脏中的生物学效应由酪氨酸激酶受体ErbB介导。在成年心脏中，NRG1由心内膜内皮细胞和心脏微血管内皮细胞表达，而受体ErbB2/ErbB4由心室心肌细胞表达，位于T小管系统和闰盘中，紧邻兴奋 - 收缩偶联的系统组件。在发现接受曲妥珠单抗（一种抗ErbB2的抑制性抗体，用于治疗乳腺癌）治疗的患者在与蒽环类药物联合使用时会出现心室功能障碍且患心肌病的风险更高之后，NRG/ErbB信号轴在心血管水平的重要性变得明显。随后的体外和体内研究阐明了成年心脏中与NRG/ErbB系统相关的效应和各自的信号通路。NRG1/ErbB系统在血管（刺激血管生成和动脉保护作用）和心肌水平（负性肌力作用）的一些心血管功能以及对心肌细胞存活、细胞生长和组织（肌原纤维组织以及心肌细胞之间的细胞间接触）的影响已被描述。此外，该系统与其他神经体液介质的相互作用也已得到研究。因此，似乎在调节交感 - 迷走平衡方面存在生理作用，并且与内皮素 - 1信号传导存在相互作用。所有这些效应都是由于NRG1与ErbB受体结合后激活了不同的细胞内信号级联反应所致。目前已确定的一些心脏信号通路包括MEK / Erk 1/2、磷脂酰肌醇3 - 激酶/ Akt、粘着斑激酶、Gab（Grb - 2相关结合蛋白）家族、血管内皮生长因子以及内皮型一氧化氮合酶产生NO等分子。因此，本文的目的是对关于NRG1/ErbB信号轴的现有信息进行最新综述，特别关注其心血管效应。
