TY - JOUR
T1 - Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling
AU - Tran, Diem Hong
AU - May, Herman I.
AU - Li, Qinfeng
AU - Luo, Xiang
AU - Huang, Jian
AU - Zhang, Guangyu
AU - Niewold, Erica
AU - Wang, Xiaoding
AU - Gillette, Thomas G.
AU - Deng, Yingfeng
AU - Wang, Zhao V.
N1 - Funding Information:
We thank the Molecular Pathology Core of University of Texas Southwestern Medical Center (UTSW, John Shelton) for help with histology. We are grateful to the Animal Resource Center of UTSW for mouse generation, breeding, and maintenance. We specially thank Dr. Marcel Mettlen (UTSW, Department of Cell biology) for help with Image J analysis. This work was supported by grants from the American Heart Association (14SDG18440002 and 17IRG33460191 to Z.V.W.), the American Diabetes Association (1-17-IBS-120, to Z.V.W.), and NIH (R01-HL137723 to Z.V.W.).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15640-y
DO - 10.1038/s41467-020-15640-y
M3 - Article
C2 - 32286306
AN - SCOPUS:85083519324
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1771
ER -