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Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism

Yuhong Wang1, Yizhe Li1, Shihong Chen1

  • 1Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Research (Washington, D.C.)
|March 19, 2025
PubMed

Insights

Gain-of-function mutations in Notch2 cause Hajdu-Cheney syndrome (HCS), leading to heart issues. This study reveals Notch2 disrupts purine metabolism in heart cells, offering a new therapeutic target for heart failure.

Area of Science:

  • Cardiovascular Biology
  • Genetic Disorders
  • Molecular Mechanisms

Background:

  • Gain-of-function mutations in Notch2 are linked to Hajdu-Cheney syndrome (HCS).
  • Congenital heart disease is common in HCS patients, but underlying mechanisms are unclear.
  • Notch2 signaling's role in cardiac function requires further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which Notch2 mutations cause cardiac dysfunction.
  • To explore the role of purine nucleotide metabolism in Notch2-mediated cardiac hypertrophy.
  • To evaluate potential therapeutic strategies targeting Notch2 signaling in heart failure.

Main Methods:

  • Generated a transgenic mouse model (hN2ICD-TgCM) expressing the human Notch2 intracellular domain (hN2ICD) in cardiomyocytes.
  • Assessed cardiac function using echocardiography and histological analysis.
  • Investigated molecular pathways involving adenylosuccinate lyase (ADSL), AMP-activated kinase (AMPK), and mTORC1.

Main Results:

  • hN2ICD-TgCM mice developed ventricular diastolic dysfunction, preserved ejection fraction, and cardiac hypertrophy.
  • Ectopic hN2ICD expression suppressed ADSL-mediated adenosine 5'-monophosphate (AMP) generation, activating mTORC1 and inhibiting AMPK.
  • Silencing HES1 or activating AMPK ameliorated cardiac hypertrophy and dysfunction in the mouse model.
  • A specific Notch2 mutation causing HCS induced cardiomyocyte hypertrophy by suppressing ADSL.

Conclusions:

  • Notch2 signaling directly impacts cardiomyocyte function by altering purine nucleotide metabolism.
  • Suppression of ADSL and subsequent AMP reduction are key mediators of Notch2-induced cardiac hypertrophy.
  • Targeting Notch2-mediated purine metabolism presents a promising therapeutic avenue for heart failure treatment.

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