| Autor: |
Li, Zhigang, Dong, Xiaxi, Zhuang, Lingfang, Jia, Kangni, Cheng, Haomai, Sun, Hang, Cui, Yuke, Ma, Wenqi, Wei, Keying, Zhang, Pupu, Xie, Hongyang, Yi, Lei, Chen, Zhiyong, Lu, Lin, Li, Tao, Zhang, Ruiyan, Yan, Xiaoxiang |
| Předmět: |
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| Zdroj: |
Science Signaling; 10/29/2024, Vol. 17 Issue 860, p1-16, 16p |
| Abstrakt: |
There is a short window during which the neonatal heart has the proliferative capacity to completely repair damage, an ability that is lost in adulthood. Inducing proliferation in adult cardiomyocytes by reactivating cell cycle reentry after myocardial infarction (MI) improves cardiac function. De novo purine synthesis is a critical source of nucleotides for cell proliferation. Here, using loss- and gain-of-function genetic approaches, we explored the role of the muscle-specific de novo purine synthesis enzyme Adssl1 in cardiac regeneration. Deletion of Adssl1 in mouse neonatal hearts reduced cardiomyocyte proliferation and attenuated heart regeneration after apical resection. Conversely, cardiomyocyte-specific Adssl1 overexpression extended the postnatal regenerative window and induced robust cell cycle reentry after MI, which decreased fibrotic scar size and improved cardiac function. RNA sequencing analysis suggested that Adssl1 overexpression induced strong dedifferentiation and cell cycle entry. Moreover, LC-MS/MS analysis showed that Adssl1 overexpression was associated with increased amounts of purine metabolites, including inosine, which is in clinical use. Administration of exogenous inosine promoted cardiac repair after MI in adult mice. At a molecular level, the increase in purine metabolite production mediated by Adssl1 enhanced the activity of the proliferation-promoting mTORC1 pathway. Our study identifies a role for Adssl1 in supporting cardiomyocyte proliferation and cardiac regeneration. Editor's summary: In contrast to the neonatal mammalian heart, in which cardiomyocyte proliferation can enable complete repair, cardiomyocytes in the adult mammalian heart must be induced to reenter the cell cycle to achieve regeneration. Increases in purine availability are required to support enhanced DNA and RNA synthesis during proliferation, leading Li et al. to investigate how cardiac regeneration is affected by Adssl1, a critical enzyme in de novo purine synthesis. Cardiac regeneration after injury in neonatal mouse heart was limited by genetic ablation of Adssl1. In contrast, the damage and impairment in cardiac function induced by myocardial infarction in adult mice were limited by overexpression of Adssl1, which promoted cell cycle reentry and proliferation in cardiomyocytes. This effect was mimicked by treatment with inosine, a purine nucleoside whose amounts were increased by Adssl1 overexpression and that is in clinical use. Thus, increasing de novo purine synthesis could be explored as a potential strategy to promote cardiac regeneration after myocardial infarction and other insults to the heart. —Wei Wong [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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