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Enhanced Aerobic Glycolysis by S‐Nitrosoglutathione via HIF‐1α Associated GLUT1/Aldolase A Axis in Human Endothelial Cells
Author(s) -
Yan Jieping,
Huang Xin,
Zhu Danyan,
Lou Yijia
Publication year - 2017
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25911
Subject(s) - s nitrosoglutathione , glut1 , aldolase a , anaerobic glycolysis , glycolysis , chemistry , biochemistry , microbiology and biotechnology , biology , glucose transporter , glutathione , endocrinology , metabolism , insulin , enzyme
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.