Document Detail


Substrate-induced up-regulation of aldose reductase by methylglyoxal, a reactive oxoaldehyde elevated in diabetes.
MedLine Citation:
PMID:  11961137     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Methylglyoxal (MG), a reactive dicarbonyl produced during glucose metabolism, induced a dose- and time-dependent increase in aldose reductase (AR) mRNA level in rat aortic smooth muscle cells (SMCs). AR has been implicated in the pathogenesis of diabetic complications, whereas the clinical efficacy of AR inhibitors has not been unequivocally proven. The enzyme catalyzes the reduction of glucose in the polyol pathway, as well as that of MG, which is known to be a preferred substrate of AR. A maximum of 4.5-fold induction of AR mRNA by MG was accompanied by elevated enzyme activity and protein levels and was completely abolished in the presence of cycloheximide or actinomycin D. Pretreatment of SMCs with N-acetyl-L-cysteine significantly suppressed the MG-induced AR expression, whereas DL-buthionine-(S,R)-sulfoximine further augmented the MG-induced increase in AR mRNA level. Intracellular levels of reactive oxygen species determined using 2',7'-dichlorofluorescein diacetate were significantly elevated in SMCs treated with MG, suggesting the involvement of oxidative stress in this process. However, inconsistent with our previous findings on oxidative stress-induced up-regulation of AR, the inhibition of extracellular signal-regulated kinase by 2'-amino-3'-methoxyflavone (PD98059) did not affect MG-induced AR expression, whereas blockade of the p38 mitogen-activated protein kinase pathway by 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl) imidazol (SB203580) significantly suppressed the induction. The cytotoxic effect of MG on SMCs was significantly enhanced in the presence of the AR inhibitor ponalrestat, indicating a protective role of AR against MG-induced cell damage. Taken together, these observations indicated that substrate-induced induction of AR by MG during hyperglycemic conditions may hinder vascular remodeling and accelerate the development of vascular lesions in diabetes.
Authors:
Ki Churl Chang; Kyung Shin Paek; Hyo Jung Kim; Young Soo Lee; Chihiro Yabe-Nishimura; Han Geuk Seo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular pharmacology     Volume:  61     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-04-18     Completed Date:  2002-05-13     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1184-91     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Gyeongsang Institute of Health Science, College of Medicine, Gyeongsang National University, Chinju, Korea.
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Reductase / genetics,  metabolism*
Animals
Cell Survival / drug effects
Diabetes Mellitus / enzymology,  metabolism*
Enzyme Activation
Mitogen-Activated Protein Kinases / metabolism
Muscle, Smooth / drug effects*,  pathology
Pyruvaldehyde / pharmacology*
RNA, Messenger / drug effects,  metabolism
Rats
Reactive Oxygen Species
Substrate Specificity
Up-Regulation / drug effects
p38 Mitogen-Activated Protein Kinases
Chemical
Reg. No./Substance:
0/RNA, Messenger; 0/Reactive Oxygen Species; 78-98-8/Pyruvaldehyde; EC 1.1.1.21/Aldehyde Reductase; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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