Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism
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| Publicado en: | Research vol. 8 (2025) |
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| Autor principal: | |
| Otros Autores: | , , , , , , , , , , , , , , , , |
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| Acceso en línea: | Citation/Abstract Full Text - PDF |
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| LEADER | 00000nab a2200000uu 4500 | ||
|---|---|---|---|
| 001 | 3254941535 | ||
| 003 | UK-CbPIL | ||
| 022 | |a 2096-5168 | ||
| 022 | |a 2639-5274 | ||
| 024 | 7 | |a 10.34133/research.0635 |2 doi | |
| 035 | |a 3254941535 | ||
| 045 | 2 | |b d20250101 |b d20251231 | |
| 100 | 1 | |a Wang, Yuhong | |
| 245 | 1 | |a Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism | |
| 260 | |c 2025 | ||
| 513 | |a Journal Article | ||
| 520 | 3 | |a 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. | |
| 653 | |a Enhancer-of-split protein | ||
| 653 | |a Hypertrophy | ||
| 653 | |a Adenylosuccinate lyase | ||
| 653 | |a Nucleotides | ||
| 653 | |a Kinases | ||
| 653 | |a Cardiomyocytes | ||
| 653 | |a TOR protein | ||
| 653 | |a Transcription activation | ||
| 653 | |a Heart diseases | ||
| 653 | |a Frameshift mutation | ||
| 653 | |a Congestive heart failure | ||
| 653 | |a AMP | ||
| 653 | |a Hereditary diseases | ||
| 653 | |a Age | ||
| 653 | |a Notch protein | ||
| 653 | |a Metabolism | ||
| 653 | |a Rapamycin | ||
| 653 | |a Animal models | ||
| 653 | |a Mutation | ||
| 653 | |a Adenosine monophosphate | ||
| 700 | 1 | |a Li, Yizhe | |
| 700 | 1 | |a Chen, Shihong | |
| 700 | 1 | |a Yu, Tingting | |
| 700 | 1 | |a Sun, Weiyan | |
| 700 | 1 | |a Liu, Jiao | |
| 700 | 1 | |a Ren, Huiwen | |
| 700 | 1 | |a Zhou, Yao | |
| 700 | 1 | |a Wang, Lu | |
| 700 | 1 | |a Tao, Xixi | |
| 700 | 1 | |a Du, Ronglu | |
| 700 | 1 | |a Shang, Wenlong | |
| 700 | 1 | |a Li, Yinxiu | |
| 700 | 1 | |a Tian, Danyang | |
| 700 | 1 | |a Wang, Bei | |
| 700 | 1 | |a Shen, Yujun | |
| 700 | 1 | |a Liu, Qian | |
| 700 | 1 | |a Yu, Ying | |
| 773 | 0 | |t Research |g vol. 8 (2025) | |
| 786 | 0 | |d ProQuest |t Science Database | |
| 856 | 4 | 1 | |3 Citation/Abstract |u https://www.proquest.com/docview/3254941535/abstract/embedded/7BTGNMKEMPT1V9Z2?source=fedsrch |
| 856 | 4 | 0 | |3 Full Text - PDF |u https://www.proquest.com/docview/3254941535/fulltextPDF/embedded/7BTGNMKEMPT1V9Z2?source=fedsrch |