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 and Zhao V. Wang ()
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Diem Hong Tran: University of Texas Southwestern Medical Center
Herman I. May: University of Texas Southwestern Medical Center
Qinfeng Li: University of Texas Southwestern Medical Center
Xiang Luo: University of Texas Southwestern Medical Center
Jian Huang: University of Texas Southwestern Medical Center
Guangyu Zhang: University of Texas Southwestern Medical Center
Erica Niewold: University of Texas Southwestern Medical Center
Xiaoding Wang: University of Texas Southwestern Medical Center
Thomas G. Gillette: University of Texas Southwestern Medical Center
Yingfeng Deng: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center
Zhao V. Wang: University of Texas Southwestern Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15640-y

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