Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism.

ABSTRACT: Gain-of-function mutations of Notch2 cause the rare autosomal dominant disorder known as Hajdu-Cheney syndrome (HCS). Most patients with HCS develop congenital heart disease; however, the precise mechanisms remain elusive. Here, a murine model expressing the human Notch2 intracellular domain (hN2ICD) in cardiomyocytes (hN2ICD-Tg^CM) was generated and the mice spontaneously developed ventricular diastolic dysfunction with preserved ejection fraction and cardiac hypertrophy. Ectopic hN2ICD expression promoted cardiomyocyte hypertrophy by suppressing adenylosuccinate lyase (ADSL)-mediated adenosine 5'-monophosphate (AMP) generation, which further enhanced the activation of the mammalian target of rapamycin complex 1 pathway by reducing AMP-activated kinase activity. Hairy and enhanc

SUBMITTER: Wang Y 

PROVIDER: S-EPMC11913782 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature