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Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism

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Publicado en:Research vol. 8 (2025)
Autor principal: Wang, Yuhong
Otros Autores: Li, Yizhe, Chen, Shihong, Yu, Tingting, Sun, Weiyan, Liu, Jiao, Ren, Huiwen, Zhou, Yao, Wang, Lu, Tao, Xixi, Du, Ronglu, Shang, Wenlong, Li, Yinxiu, Tian, Danyang, Wang, Bei, Shen, Yujun, Liu, Qian, Yu, Ying
Publicado:
Materias:
Enhancer-of-split protein
Hypertrophy
Adenylosuccinate lyase
Nucleotides
Kinases
Cardiomyocytes
TOR protein
Transcription activation
Heart diseases
Frameshift mutation
Congestive heart failure
AMP
Hereditary diseases
Age
Notch protein
Metabolism
Rapamycin
Animal models
Mutation
Adenosine monophosphate
Acceso en línea:Citation/Abstract
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Resumen: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 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-Tg CM 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:2096-5168
2639-5274
DOI:10.34133/research.0635
Fuente:Science Database