Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

Diem Hong Tran, Herman I. May, Qinfeng Li, Xiang Luo, Jian Huang, Guangyu Zhang, Erica Niewold, Xiaoding Wang, Thomas G. Gillette, Yingfeng Deng, Zhao V. Wang

Research output: Contribution to journalArticle

Abstract

The hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth. However, its contribution to cardiac hypertrophic growth and heart failure remains incompletely understood. Here, we show that the HBP is induced in cardiomyocytes during hypertrophic growth. Overexpression of Gfat1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of HBP, promotes cardiomyocyte growth. On the other hand, Gfat1 inhibition significantly blunts phenylephrine-induced hypertrophic growth in cultured cardiomyocytes. Moreover, cardiac-specific overexpression of Gfat1 exacerbates pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, deletion of Gfat1 in cardiomyocytes attenuates pathological cardiac remodeling in response to pressure overload. Mechanistically, persistent upregulation of the HBP triggers decompensated hypertrophy through activation of mTOR while Gfat1 deficiency shows cardioprotection and a concomitant decrease in mTOR activity. Taken together, our results reveal that chronic upregulation of the HBP under hemodynamic stress induces pathological cardiac hypertrophy and heart failure through persistent activation of mTOR.

Original languageEnglish (US)
Article number1771
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Tran, D. H., May, H. I., Li, Q., Luo, X., Huang, J., Zhang, G., Niewold, E., Wang, X., Gillette, T. G., Deng, Y., & Wang, Z. V. (2020). Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling. Nature communications, 11(1), [1771]. https://doi.org/10.1038/s41467-020-15640-y