Metabolic regulation of aldose reductase activity by nitric oxide donors

Regulation of aldose reductase (AR), a member of the aldo-keto reductase su perfamily, by nitric oxide (NO) donors was examined. Incubation of human re combinant AR with S-nitrosoglutathione (GSNO) led to inactivation of the en zyme and the formation of an AR-glutathione adduct. In contrast, incubation with S-nitroso-N-acetyl penicillamine (SNAP) or N-(beta -D-glucopyranosyl) -SNAP (GlycoSNAP) led to an increase in enzyme activity which was accompani ed by the direct nitrosation of the enzyme and the formation of a mixed dis ulfide with the NO-donor. To examine in vivo modification, red blood cells (RBC) and rat aortic vascular smooth muscle cells (VSMC) were incubated wit h 1 mM GSNO or SNAP. Exposure of VSMC to SNAP and GSNO for 2 h at 37 degree sC led to similar to 71% decrease in the enzyme activity with DL-glyceralde hyde as the substrate. Similarly, exposure of RBC in 5 mM glucose to NO-don ors for 30 min at room temperature, followed by increasing the glucose conc entration to 40 mM, resulted in > 75% decrease in the formation of; sorbito l. These investigations indicate that NO and/or ifs bioactive metabolites c an regulate cellular AR, leading to either activation (by nitrosation) or i nactivation (by S-thiolation). (C) 2001 Elsevier Science Ireland Ltd. All r ights reserved.