Activation of Notch-mediated protective signaling in the myocardium

Circ Res. 2008 May 9;102(9):1025-35. doi: 10.1161/CIRCRESAHA.107.164749. Epub 2008 Mar 27.


The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades. The impact of HGF on Notch signaling was assessed following myocardial infarction as well as in cultured cardiomyocytes. Notch1 is activated in border zone cardiomyocytes coincident with nuclear c-Met following infarction. Intramyocardial injection of HGF enhances Notch1 and Akt activation in adult mouse myocardium. Corroborating evidence in cultured cardiomyocytes shows treatment with HGF or insulin increases levels of Notch effector Hes1 in immunoblots, whereas overexpression of activated Notch intracellular domain prompts a 3-fold increase in phosphorylated Akt. Infarcted hearts injected with adenoviral vector expressing Notch intracellular domain treatment exhibit improved hemodynamic function in comparison with control mice after 4 weeks, implicating Notch signaling in a cardioprotective role following cardiac injury. These results indicate Notch activation in cardiomyocytes is mediated through c-Met and Akt survival signaling pathways, and Notch1 signaling in turn enhances Akt activity. This mutually supportive crosstalk suggests a positive survival feedback mechanism between Notch and Akt signaling in adult myocardium following injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Activation
  • Feedback, Physiological
  • Female
  • Hemodynamics
  • Hepatocyte Growth Factor / metabolism
  • Homeodomain Proteins / metabolism
  • Insulin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Notch1 / metabolism
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Signal Transduction*
  • Time Factors
  • Transcription Factor HES-1
  • Transduction, Genetic


  • Basic Helix-Loop-Helix Transcription Factors
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Insulin
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Receptors, Notch
  • Transcription Factor HES-1
  • Hepatocyte Growth Factor
  • RON protein
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt