Abstract
Neuregulin1 proteins (NRG1s) are epidermal growth factor (EGF) family members which are ligands for the ErbB receptor tyrosine kinases (RTKs). A decade of research has revealed that the NRG1-ErbB signaling is essential for the cardiac development and pivotal for maintaining the physiological function of the adult heart. The first evidence regarding the protective effect of the ErbB2 signaling in the adult heart came from clinical trials in breast cancer patients using Trastuzumab, a monoclonal antibody that blocks the ErbB2 receptor. The incidence of the New York Heart Association (NYHA) class III/IV heart failure increased five-fold in patients treated concurrently with chemotherapy drug doxorubicin and Trastuzumab compared to those treated with doxorubicin alone. Subsequent studies further show that stimulation of the ErbB2 signaling by NRG1s improves cardiomyocyte survival, growth and proliferation, maintains cardiac myofibril structure, counterbalances excessive β-adrenergic signaling and promotes angiogenesis in the heart. Injections of recombinant NRG1s improve cardiac function in animal models with myocardial infarction, doxorubicin, viral infection or pacing -induced heart failure. Recent clinical trials show that NRG1s are effective for improving the cardiac function in heart failure patients. These results suggest that NRG1s may become a new drug for the treatment of heart failure. NRG1s stimulate RTKs. This is different from Beta-blockers, ACE inhibitors (Angiotensin-Converting Enzyme) and Angiotensin II receptor blockers which inhibit the excessive activation of G-protein coupled receptors (GPCRs). A clear understanding of how NRG1-ErbB signaling regulates cardiac function is essential for successful use of NRG1s for heart failure. Here, we review the current knowledge of the NRG1-ErbB signaling in the heart and discuss the potential use of NRG1s as novel therapy for heart failure.
Keywords: Neuregulin, growth factor, heart failure, ErbB, receptor tyrosine kinases, tyrosine, kinases, Beta-blockers, doxorubicin, stimulate, chemotherapy, adrenergic, counterbalancing, phenotype, ectodermal, reminiscent, trabecula, metalloproteases
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