Aldolase B Knockdown Prevents High Glucose-Induced Methylglyoxal Overproduction and Cellular Dysfunction in Endothelial Cells

被引:20
作者
Liu, Jianghai [1 ]
Mak, Timothy Chun-Ping [1 ]
Banigesh, Ali [1 ]
Desai, Kaushik [1 ]
Wang, Rui [2 ]
Wu, Lingyun [1 ,3 ,4 ]
机构
[1] Univ Saskatchewan, Dept Pharmacol, Coll Med, Saskatoon, SK S7N 0W0, Canada
[2] Lakehead Univ, Dept Biol, Thunder Bay, ON P7B 5E1, Canada
[3] Lakehead Univ, Dept Hlth Sci, Thunder Bay, ON P7B 5E1, Canada
[4] Thunder Bay Reg Res Inst, Thunder Bay, ON, Canada
基金
加拿大健康研究院;
关键词
GLYCATION END-PRODUCTS; SMOOTH-MUSCLE-CELLS; PROTEIN-KINASE-C; NF-KAPPA-B; DEPENDENT PATHWAY; ALDOSE REDUCTASE; OXIDATIVE STRESS; DIABETIC-RATS; GROWTH-FACTOR; NITRIC-OXIDE;
D O I
10.1371/journal.pone.0041495
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We used cultured endothelial cells as a model to examine whether up-regulation of aldolase B and enhanced methylglyoxal (MG) formation play an important role in high glucose-induced overproduction of advanced glycosylation endproducts (AGEs), oxidative stress and cellular dysfunction. High glucose (25 mM) incubation up-regulated mRNA levels of aldose reductase (an enzyme converting glucose to fructose) and aldolase B (a key enzyme that catalyzes MG formation from fructose) and enhanced MG formation in human umbilical vein endothelial cells (HUVECs) and HUVEC-derived EA. hy926 cells. High glucose-increased MG production in EA. hy926 cells was completely prevented by siRNA knockdown of aldolase B, but unaffected by siRNA knockdown of aldolase A, an enzyme responsible for MG formation during glycolysis. In addition, inhibition of cytochrome P450 2E1 or semicarbazide-sensitive amine oxidase which produces MG during the metabolism of lipid and proteins, respectively, did not alter MG production. Both high glucose (25 mM) and MG (30, 100 mu M) increased the formation of N(epsilon)-carboxyethyl-lysine (CEL, a MG-induced AGE), oxidative stress (determined by the generation of oxidized DCF, H2O2, protein carbonyls and 8-oxo-dG), O-GlcNAc modification (product of the hexosamine pathway), membrane protein kinase C activity and nuclear translocation of NF-kappa B in EA. hy926 cells. However, the above metabolic and signaling alterations induced by high glucose were completely prevented by knockdown of aldolase B and partially by application of aminoguanidine (a MG scavenger) or alagebrium (an AGEs breaker). In conclusion, efficient inhibition of aldolase B can prevent high glucose-induced overproduction of MG and related cellular dysfunction in endothelial cells.
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页数:10
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