RT Journal Article
SR Electronic
T1 Substrate-Induced Up-Regulation of Aldose Reductase by Methylglyoxal, a Reactive Oxoaldehyde Elevated in Diabetes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1184
OP 1191
DO 10.1124/mol.61.5.1184
VO 61
IS 5
A1 Ki Churl Chang
A1 Kyung Shin Paek
A1 Hyo Jung Kim
A1 Young Soo Lee
A1 Chihiro Yabe-Nishimura
A1 Han Geuk Seo
YR 2002
UL http://molpharm.aspetjournals.org/content/61/5/1184.abstract
AB 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 withN-acetyl-l-cysteine significantly suppressed the MG-induced AR expression, whereasdl-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.