ErbB2-NOTCH1 axis controls autophagy in cardiac cells

Area of Science:

• Cardiovascular Biology
• Molecular Cell Biology
• Pharmacology

Background:

• Epidermal growth factor receptor 2 (ErbB2) and Notch1 signaling pathways are crucial for cardiac function.
• The interplay between ErbB2 and Notch1 in the heart is not well understood.

Purpose of the Study:

• To investigate the crosstalk between ErbB2 and Notch1 signaling in cardiac cells.
• To determine the effects of this crosstalk on autophagy and cell proliferation.
• To explore the implications for ErbB2-targeting drug cardiotoxicity.

Main Methods:

• Utilized H9c2 cardiomyoblasts and primary neonatal mouse cardiomyocytes.
• Employed ErbB2 overexpression and inhibition (lapatinib).
• Assessed Notch1 activation, autophagic flux, proliferation, and gene expression in transgenic mice.

Main Results:

• ErbB2 overexpression activated Notch1 in a p38-dependent manner.
• ErbB2 inhibition (lapatinib) reduced Notch1 activation, stalled autophagy, and decreased proliferation.
• Neuregulin-1 stimulation of ErbB2 in cardiomyocytes increased proliferation, an effect blocked by Notch1 inhibition.
• Transgenic mice overexpressing ErbB2 showed increased active Notch1 and Notch-related gene levels.

Conclusions:

• Demonstrated a functional crosstalk between ErbB2 and Notch1 signaling in cardiac cells.
• Highlighted the role of this interaction in regulating autophagy and proliferation.
• Provided mechanistic insights into the cardiotoxicity of ErbB2-targeting cancer therapies.