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Kynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis

Author

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  • Donghong Zhang

    (Center for Molecular and Translational Medicine, Georgia State University)

  • Jinfeng Ning

    (Center for Molecular and Translational Medicine, Georgia State University)

  • Tharmarajan Ramprasath

    (Center for Molecular and Translational Medicine, Georgia State University)

  • Changjiang Yu

    (Center for Molecular and Translational Medicine, Georgia State University)

  • Xiaoxu Zheng

    (Center for Molecular and Translational Medicine, Georgia State University)

  • Ping Song

    (Center for Molecular and Translational Medicine, Georgia State University)

  • Zhonglin Xie

    (Center for Molecular and Translational Medicine, Georgia State University)

  • Ming-Hui Zou

    (Center for Molecular and Translational Medicine, Georgia State University)

Abstract

Indoleamine 2,3 dioxygenase-1 (IDO1) catalyzes tryptophan-kynurenine metabolism in many inflammatory and cancer diseases. Of note, acute inflammation that occurs immediately after heart injury is essential for neonatal cardiomyocyte proliferation and heart regeneration. However, the IDO1-catalyzed tryptophan metabolism during heart regeneration is largely unexplored. Here, we find that apical neonatal mouse heart resection surgery led to rapid and consistent increases in cardiac IDO1 expression and kynurenine accumulation. Cardiac deletion of Ido1 gene or chemical inhibition of IDO1 impairs heart regeneration. Mechanistically, elevated kynurenine triggers cardiomyocyte proliferation by activating the cytoplasmic aryl hydrocarbon receptor-SRC-YAP/ERK pathway. In addition, cardiomyocyte-derived kynurenine transports to endothelial cells and stimulates cardiac angiogenesis by promoting aryl hydrocarbon receptor nuclear translocation and enhancing vascular endothelial growth factor A expression. Notably, Ahr deletion prevents indoleamine 2,3 dioxygenase -kynurenine–associated heart regeneration. In summary, increasing indoleamine 2,3 dioxygenase-derived kynurenine level promotes cardiac regeneration by functioning as an endogenous regulator of cardiomyocyte proliferation and cardiac angiogenesis.

Suggested Citation

  • Donghong Zhang & Jinfeng Ning & Tharmarajan Ramprasath & Changjiang Yu & Xiaoxu Zheng & Ping Song & Zhonglin Xie & Ming-Hui Zou, 2022. "Kynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33734-7
    DOI: 10.1038/s41467-022-33734-7
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    1. Wenya Ma & Yanan Tian & Leping Shi & Jing Liang & Qimeng Ouyang & Jianglong Li & Hongyang Chen & Hongyue Sun & Haoyu Ji & Xu Liu & Wei Huang & Xinlu Gao & Xiaoyan Jin & Xiuxiu Wang & Yining Liu & Yang, 2024. "N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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