Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism

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.