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Vol. 57, Issue 4, 709-717, April 2000

Nitric Oxide Up-Regulates Aldose Reductase Expression in Rat Vascular Smooth Muscle Cells: A Potential Role for Aldose Reductase in Vascular Remodeling

Han Geuk Seo,1 Toru Nishinaka, and Chihiro Yabe-Nishimura

Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Acceleration of the polyol pathway under hyperglycemia is among the mechanisms implicated in the pathogenesis of diabetic complications. Although aldose reductase (AR), the rate-limiting enzyme in this pathway, is a target for pharmacological intervention of diabetic complications, the clinical efficacy of AR inhibitors has not been consistently proved. Because nitric oxide (NO) plays important roles in vascular hemodynamics and inflammatory responses that are affected under diabetic conditions, the interaction of NO with AR was investigated with rat aortic smooth muscle cells. Spontaneous NO donors, S-nitroso-N-acetylpenicillamine (SNAP) and 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine, elicited a dose-dependent increase in AR mRNA to a maximum of 7-fold in 12 h. The activity of AR was elevated after 10 h of SNAP treatment. These effects of NO donors were suppressed by the addition of 2-(trimethylammoniophenyl)-4,4,5,5-tetramethylimidazoline-1-oxy 3-oxide, a scavenger of NO. Induction of AR mRNA by SNAP was completely abolished by actinomycin D or cycloheximide, but unaffected by guanylate cyclase inhibitors or genistein, a tyrosine kinase inhibitor. Pretreatment of the cells with N-acetyl-L-cysteine significantly suppressed the SNAP-induced up-regulation of AR mRNA. Under normal glucose conditions, inclusion of the AR inhibitor ponalrestat augmented the cytotoxic effect of SNAP on the cells. The level of AR mRNA also was elevated in a murine macrophage cell line RAW 264.7 stimulated with lipopolysaccharide and interferon-gamma . Inhibition of NO synthesis completely abolished the increase in AR mRNA in the stimulated cells. The up-regulation of AR by NO in the vascular lesions may modulate NO-induced cell death and the ensuing vascular remodeling during inflammatory responses.

1 Current address: Department of Pharmacology, School of Medicine, Gyeongsang National University, Chinju 660-751, Korea.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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