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.
Highlights
The hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth
Treatment by IGF-1, Endothelin-1 (ET-1), or Angiotensin II (Ang II) in neonatal rat ventricular myocytes (NRVMs) led to hypertrophic growth and concomitant increases in genes of the HBP (Supplementary Fig. 2a–c)
PE-induced hypertrophic growth in adult cardiomyocytes (Supplementary Fig. 3a) was associated with a significant increase of glutamine:fructose-6-phosphate amidotransferase (Gfat)[1] expression (Supplementary Fig. 3b). These findings suggest that cardiomyocyte hypertrophic growth is associated with significant upregulation of the HBP
Summary
The hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth. Intracellular glucose may be shunted to other metabolic pathways, including the HBP Consistent with this notion, elevation of cardiac UDP-GlcNAc has been discovered in rats by pressure overload[23]. Gelinas et al.[25] showed that 5′-adenosine monophosphate-activated protein kinase (AMPK) prevents pathological cardiac hypertrophy by promoting Gfat[1] phosphorylation and thereby decreasing OGlcNAc modification in the heart. Despite these findings, it remains to be answered whether the upregulation of HBP by pressure overload plays a causal role in pathological cardiac remodeling. Mechanistic/mammalian target of rapamycin (mTOR) is an atypical protein kinase, consisting of two distinct complexes to integrate multiple metabolic signals and govern cell growth[26]
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