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Activation of Notch-mediated protective signaling in the myocardium

Natalie A Gude1, Gregory Emmanuel, Weitao Wu

  • 1San Diego State University Heart Institute, Department of Biology, San Diego State University, San Diego, CA 92182, USA.

Circulation Research
|March 29, 2008
PubMed

Insights

Hepatocyte growth factor (HGF) activates Notch signaling in heart cells via the c-Met and Akt pathways. This Notch-Akt crosstalk promotes survival and improves heart function after cardiac injury.

Area of Science:

  • Cardiovascular Biology
  • Molecular and Cellular Biology
  • Regenerative Medicine

Background:

  • The Notch network is crucial for cellular processes like differentiation, proliferation, and regeneration.
  • Notch signaling interacts with hepatocyte growth factor (HGF)/c-Met and phosphatidylinositol 3-kinase/Akt pathways.
  • Understanding these interactions is key to developing therapies for cardiac injury.

Purpose of the Study:

  • To investigate the impact of HGF on Notch signaling in cardiomyocytes following myocardial infarction.
  • To elucidate the role of Notch signaling in cardiac repair and cardioprotection.
  • To explore the crosstalk between Notch and Akt survival pathways in the adult myocardium.

Main Methods:

  • Assessment of Notch1 and c-Met activation in cardiomyocytes post-myocardial infarction in mice.
  • Intramyocardial injection of HGF and analysis of Notch1 and Akt activation.
  • In vitro studies using cultured cardiomyocytes treated with HGF or insulin, and overexpression of Notch intracellular domain.

Main Results:

  • Notch1 activation was observed in cardiomyocytes near the infarction border zone, coinciding with nuclear c-Met.
  • HGF treatment enhanced Notch1 and Akt activation in adult mouse myocardium and increased Hes1 levels in cultured cardiomyocytes.
  • Overexpression of Notch intracellular domain improved hemodynamic function in infarcted hearts, indicating a cardioprotective role.

Conclusions:

  • Notch activation in cardiomyocytes is mediated by c-Met and Akt survival signaling.
  • Notch1 signaling positively regulates Akt activity, forming a survival feedback loop.
  • This Notch-Akt crosstalk represents a critical survival mechanism in the adult myocardium following injury.

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