Increased production of methylglyoxal (MG) in vascular tissues is one of the causative factors for vascular remodelling in different subtypes of metabolic syndrome, including hypertension and insulin resistance. Fructose-induced up-regulation of aldolase B (AldoB) contributes to increased vascular MG production but the underlying mechanisms are unclear. Serum levels of MG and fructose were determined in diabetic patients with hypertension. MG level had significant positive correlations with blood pressure and fructose level respectively. C57BL/6 mice were fed with control or fructose-enriched diet for 3 months and ultrasonographic and histologic analyses were performed to evaluate arterial structural changes. Fructose-fed mice exhibited hypertension and high levels of serum MG with normal glucose level. Fructose intake increased blood vessel wall thickness and vascular smooth muscle cell (VSMC) proliferation. Western blotting and real-time PCR analysis revealed that AldoB level was significantly increased in both the aorta of fructose-fed mice and the fructose-treated VSMCs, whereas aldolase A (AldoA) expression was not changed. The knockdown of AldoB expression prevented fructose-induced MG overproduction and VSMC proliferation. Moreover, fructose significantly increased carbohydrate-responsive element-binding protein (ChREBP), phosphorylated FoxO1/3α and Akt1 levels. Fructose induced translocation of ChREBP from the cytosol to nucleus and activated AldoB gene expression, which was inhibited by the knockdown of ChREBP. Meanwhile, fructose caused FoxO1/3α shuttling from the nucleus to cytosol and inhibited its binding to AldoB promoter region. Fructose-induced AldoB up-regulation was suppressed by Akt1 inhibitor but enhanced by FoxO1/3α siRNA. Collectively, fructose activates ChREBP and inactivates FoxO1/3α pathways to up-regulate AldoB expression and MG production, leading to vascular remodelling.
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February 2017
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Density-dependent scanning electron microscopy of calcifying vascular tissue (orange - calcification; green - collagen). Please see pp. 181-195 for more information. Image provided by Sergio Bertazzo.
Research Article|
January 30 2017
Dual effects of fructose on ChREBP and FoxO1/3α are responsible for AldoB up-regulation and vascular remodelling
Wei Cao;
Wei Cao
*Department of Health Sciences, Lakehead University, Thunder Bay, Canada P7B 5E1
†School of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, China
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Tuanjie Chang;
Tuanjie Chang
‡Thunder Bay Regional Research Institute, Thunder Bay, Canada P7A 7T1
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Xiao-qiang Li;
Xiao-qiang Li
§Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
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Rui Wang;
Rui Wang
∥Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, Canada P7A 7T1
¶Cardiovascular and Metabolic Research Unit, Laurentian University, Canada P3E 2C6
**Department of Biology, Laurentian University, Canada P3E 2C6
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Lingyun Wu
*Department of Health Sciences, Lakehead University, Thunder Bay, Canada P7B 5E1
¶Cardiovascular and Metabolic Research Unit, Laurentian University, Canada P3E 2C6
††Health Sciences North Research Institute, Sudbury, Canada P3E 5J1
Correspondence: Lingyun Wu ([email protected])
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Publisher: Portland Press Ltd
Received:
April 03 2016
Revision Received:
December 04 2016
Accepted:
December 21 2016
Accepted Manuscript online:
December 22 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (4): 309–325.
Article history
Received:
April 03 2016
Revision Received:
December 04 2016
Accepted:
December 21 2016
Accepted Manuscript online:
December 22 2016
Citation
Wei Cao, Tuanjie Chang, Xiao-qiang Li, Rui Wang, Lingyun Wu; Dual effects of fructose on ChREBP and FoxO1/3α are responsible for AldoB up-regulation and vascular remodelling. Clin Sci (Lond) 1 February 2017; 131 (4): 309–325. doi: https://doi.org/10.1042/CS20160251
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