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ErbB2-NOTCH1 axis controls autophagy in cardiac cells

Francesca Fortini1, Francesco Vieceli Dalla Sega1, Edoardo Lazzarini2,3

  • 1GVM Care & Research, Maria Cecilia Hospital, Ravenna, Italy.

Biofactors (Oxford, England)
|July 12, 2024
PubMed

Insights

Epidermal growth factor receptor 2 (ErbB2) and Notch1 signaling pathways crosstalk in cardiac cells, impacting autophagy and proliferation. This interaction may explain cardiotoxicity from ErbB2-targeting cancer drugs.

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.
Keywords:
ErbB2Notchautophagycardiomyocytesheart

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