Suppression of 3-deoxyglucosone and heparin-binding epidermal growth factor-like growth factor mRNA expression by an aldose reductase inhibitor in rat vascular smooth muscle cells.
Reactive carbonyl compounds and oxidative stress have been recently shown to up-regulate the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen for vascular smooth muscle cells (SMCs) produced by SMC themselves. Because the polyol pathway has been reported to influence the formation of carbonyl compounds and the oxidative stress in various cells, we conducted this study to investigate whether the polyol pathway affects HB-EGF expression along with the generation of carbonyl compounds and the oxidative stress in SMCs. We found that, compared with those cultured with 5.5mM glucose, SMCs cultured with 40 mM glucose showed the accelerated thymidine incorporation, elevated levels of intracellular sorbitol, 3-deoxyglucosone (3-DG), advanced glycation end products (AGEs), and thiobarbituric acid-reactive substances (TBARS) along with the enhanced expression of HB-EGF mRNA. An aldose reductase inhibitor (ARI), SNK-860, significantly inhibited all of these abnormalities, while aminoguanidine suppressed 3-DG levels and HB-EGF mRNA expression independent of sorbitol levels. The results suggest that the polyol pathway may play a substantial role in SMC hyperplasia under hyperglycemic condition in part by affecting HB-EGF mRNA expression via the production of carbonyl compounds and oxidative stress.
Li
Weiguo
W
Division of Metabolic Diseases, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Hamada
Yoji
Y
Nakashima
Eitaro
E
Naruse
Keiko
K
Kamiya
Hideki
H
Akiyama
Noboru
N
Hirooka
Hiroko
H
Takahashi
Naoki
N
Horiuchi
Seikoh
S
Hotta
Nigishi
N
Oiso
Yutaka
Y
Nakamura
Jiro
J
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013012:Sorbitol / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances; D013936:Thymidine / Q000378:metabolism / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D007093:Imidazoles; D048289:Imidazolidines; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D013012:Sorbitol; D004815:Epidermal Growth Factor; C077139:fidarestat; D003847:Deoxyglucose; D000449:Aldehyde Reductase; C016350:3-deoxyglucosone; D005947:Glucose; D013936:Thymidine