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Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling
Diem Hong Tran1, Herman I May1, Qinfeng Li1,2
1Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Insights
The hexosamine biosynthetic pathway (HBP) drives heart growth and failure. Inhibiting its enzyme Gfat1 protects the heart from stress-induced damage by reducing mTOR activity.
Area of Science:
- Cardiovascular Biology
- Metabolic Pathways
- Cellular Signaling
Background:
- The hexosamine biosynthetic pathway (HBP) is crucial for nutrient sensing and cell growth.
- Its role in pathological cardiac hypertrophy and heart failure is not fully understood.
Purpose of the Study:
- To investigate the HBP's contribution to cardiac hypertrophic growth and heart failure.
- To elucidate the molecular mechanisms linking HBP to cardiac remodeling.
Main Methods:
- Utilized cell culture models of cardiomyocytes and in vivo mouse models.
- Manipulated the expression of Gfat1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of HBP.
- Assessed cardiac hypertrophy, fibrosis, cardiac function, and mTOR signaling.
Main Results:
- HBP is upregulated in cardiomyocytes during hypertrophic growth.
- Gfat1 overexpression promotes cardiomyocyte growth and exacerbates pressure overload-induced cardiac dysfunction.
- Gfat1 inhibition or deletion attenuates cardiac hypertrophy and fibrosis, reducing mTOR activity.
Conclusions:
- Chronic HBP upregulation under hemodynamic stress induces pathological cardiac hypertrophy and heart failure.
- This process is mediated by persistent activation of mTOR.
- Targeting Gfat1 and the HBP offers a potential therapeutic strategy for heart failure.
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.
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