Cardioprotective Role of Neuregulin1–ErbB2 Signaling Pathway: Its Physiological and Onco-Cardiological Roles in the Heart

Neuregulin 1 (NRG1), a member of the epidermal growth factor (EGF) family, regulates the development, differentiation, proliferation, and plasticity in multiple tissues through its binding to ErbB3 and ErbB4 receptors. In the cardiovascular system, NRG1 plays a crucial role in cardiac development, physiological function, and cell survival. Since NRG1 exerts cardioprotective effects through its interaction with ErbB2/ErbB4 and ErbB4 homodimers on cardiomyocytes, the administration of recombinant human NRG1 has the potential for the treatment of heart failure. ErbB2 is known as human epidermal growth factor receptor 2 (HER2), which is overexpressed in approximately 20% of breast cancers. Trastuzumab (TRZ), a humanized monoclonal antibody targeting ErbB2/HER2, is used for the therapy of HER2-positive breast cancer. However, cardiotoxicity has been observed in approximately 5-10% of patients treated with TRZ. Risk factors for the onset of cardiotoxicity include the use of anthracyclines, hypertension, and diabetes. However, the mechanism linking diabetes and TRZ-induced cardiotoxicity remains unclear. Recently, we reported that the serum levels of NRG1 were elevated in the mouse model of diabetic cardiomyopathy. We found that the up-regulated NRG1 compensates for insulin deficiency to maintain systolic function in the early stage of diabetic cardiomyopathy. This review aims to discuss the physiological roles of NRG1-ErbB2 signaling in the cardiovascular system, the cardioprotective effects of NRG1 and its clinical applications, and the molecular mechanisms of TRZ-induced cardiotoxicity through the blockade of the NRG1-ErbB2 signaling pathway.