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. 2017 Aug;118(8):2443-2453.
doi: 10.1002/jcb.25911. Epub 2017 Apr 25.

Enhanced Aerobic Glycolysis by S-Nitrosoglutathione via HIF-1α Associated GLUT1/Aldolase A Axis in Human Endothelial Cells

Jieping Yan  1   2 , Xin Huang  3 , Danyan Zhu  1 , Yijia Lou  1
Affiliations

Enhanced Aerobic Glycolysis by S-Nitrosoglutathione via HIF-1α Associated GLUT1/Aldolase A Axis in Human Endothelial Cells

Jieping Yan et al. J Cell Biochem. 2017 Aug.

Abstract

S-nitrosoglutathione (GSNO)-induced apoptosis is associated with reactive oxygen species and loss of mitochondrial Omi/HtrA2 in human endothelial cells (ECs). But its upstream regulation is still not elucidated. Here, we demonstrate that hypoxia induced factor-1α (HIF-1α)-linked aerobic glycolysis is associated with mitochondrial abnormality by treatment of human EC-derived EA.hy926 cells with GSNO (500 µM) for 6 h. GSNO exposure increased the levels of Aldolase A and glucose transporter-1 (GLUT1) mRNAs and proteins. And selectively enhanced aldolase A activity to form glyceraldehyde 3-phosphate, dihydroxyacetone phosphate, which subsequently increased intracellular levels of methylglyoxal and reactive oxygen species in parallel. Using the biotin switch assay, we found that GSNO increased the S-nitrosylating levels of total protein and HIF-1α. Knockdown of HIF-1α with siRNA attenuated its target aldolase A and GLUT1 expression but not VEGF. In contrast, nitrosylation scanvenger dithiothreitol could decrease all the protein levels. It suggested that aerobic glycolytic flux was more dependent on HIF-1α level, and that HIF-1α S-nitrosylation was crucial for its target expression under the normoxic condition. Moreover, GSNO-induced PI3 K (phosphoinositide 3-kinase)/Akt phosphorylation might contribute to HIF-1α stabilization and nucleus translocation, thereby aiding aldolase A and GLUT1 mRNAs upregulation. Taken together, higher concentration GSNO promotes glycolytic flux enhancement and methylglyoxal formation via HIF-1α S-nitrosylation. These findings reveal the mechanism of enhanced glycolysis-associated mitochondrial dysfunction in ECs by GSNO exposure under normoxic and non-hyperglycemic condition. And offer the early potential targets for vascular pathophysiological evaluation. J. Cell. Biochem. 118: 2443-2453, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: AEROBIC GLYCOLYSIS; GLUT1/ALDOLASE A AXIS; HIF-1α S-NITROSYLATION; MITOCHONDRIA; S-NITROSOGLUTATHIONE.

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