Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism

Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism

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...

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Main Authors: Yuhong Wang, Yizhe Li, Shihong Chen, Tingting Yu, Weiyan Sun, Jiao Liu, Huiwen Ren, Yao Zhou, Lu Wang, Xixi Tao, Ronglu Du, Wenlong Shang, Yinxiu Li, Danyang Tian, Bei Wang, Yujun Shen, Qian Liu, Ying Yu
Format: Article
Language:English
Published: American Association for the Advancement of Science (AAAS) 2025-01-01
Series:Research
Online Access:https://spj.science.org/doi/10.34133/research.0635
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Summary: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-TgCM) 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 enhancer of split 1 silencing abrogated hN2ICD-induced cardiomyocyte hypertrophy by increasing Adsl transcription. Importantly, pharmacological activation of AMP-activated kinase ameliorated cardiac hypertrophy and dysfunction in hN2ICD-TgCM mice. The frameshift mutation in Notch2 exon 34 (c.6426dupT), which causes early-onset HCS, induces AC16 human cardiomyocyte hypertrophy through suppressing ADSL-mediated AMP generation. Thus, targeting Notch2-mediated purine nucleotide metabolism may be an attractive therapeutic approach to heart failure treatment.
ISSN:2639-5274

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