The epidermal growth factor (EGF) receptor family network in cardiac hypertrophy and heart failure
Year: 2026
Type: preprint
Abstract: The epidermal growth factor receptor (EGFR) network comprises 4 receptors (EGFR, ERBB2, ERBB3, ERBB4) and multiple ligands (EGFR-Ls; for example, AREG/EGF/TGFA that bind to EGFR, EREG/HBEGF that bind to EGFR/ERBB3, and NRG1 that binds to ERBB3/4). NRG1 and ERBB2/ERBB4 are cardioprotective, whilst other EGFR-Ls are implicated in cardiomyocyte hypertrophy. We sought to understand the importance of this network in human heart failure and development of cardiac hypertrophy. By mining data from the Human Protein Atlas, we established that the EGFR family and EGFR-Ls are expressed in different cardiac cells. Furthermore, EGFR-L mRNAs were modulated in failing vs non-failing human hearts implicating them in end-stage disease. In rat cardiomyocytes, EGFR-Ls all activated extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt. However, NRG1 preferentially activated Akt whereas AREG/EREG/HBEGF/TGFA preferentially activated ERK1/2. EGF and NRG1 differentially regulated early gene expression with the response to NRG1 having a greater requirement for ERBB2. To determine if the network is involved in developing cardiac hypertrophy, mice were treated with angiotensin II (AngII) without/with afatinib (to inhibit all EGFR family members). Expression of EGFR-L mRNAs was modulated by AngII over 3-7d. At 7d, echocardiography and segmental strain analysis identified greater cardiac dysfunction in hearts from mice treated with afatinib/AngII compared with AngII alone, associated with inhibition of cardiomyocyte hypertrophy and enhanced cardiac fibrosis. In conclusion, the EGFR network plays an important role in cardiomyocyte and cardiac hypertrophy and is dysregulated in human failing hearts. Further insight into the network may enable identification of novel therapies for cardiac disorders. Clinical perspectives The epidermal growth factor receptor (EGFR) network is is potentially important for cardioprotection and cardiac hypertrophy. The EGFR family and their ligands (EGFR-Ls) were differentially expressed in human cardiac cells with changes in EGFR-Ls in human heart failure. EGFR-Ls had differential effects on cardiomyocyte signalling/gene expression and were modulated in cardiomyocyte and cardiac hypertrophy. Inhibition of EGFRs in a mouse model of hypertrophy reduced cardiac/cardiomyocyte hypertrophy, enhanced fibrosis and caused cardiac dysfunction. The EGFR network is important for cardiomyocyte/cardiac hypertrophy and is dysregulated in human failing hearts. Intervention in this system may offer opportunities to alleviate disease progression.
Institutions: University of Reading, University of Oxford
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7161708995