Dysfunction in nitric oxide synthesis in streptozotocin treated rat aorta and role of methylglyoxal

Diabetic vascular dysfunction is a major complication of diabetes. Methylglyoxal (MGO) is a dicarbonyl metabolite elevated in diabetic plasma that reacts with interstitial molecules to form advanced glycation end products (AGE). We investigated whether MGO affects the release of nitric oxide (NO) from rat aortic smooth muscle cells (ASMCs), and if L-arginine can prevent these effects of MGO. MGO was significantly elevated in serum from streptozotocin (STZ)-treated rats (121 +/- 11.2 mu M) compared with vehicle control rats (27.5 +/- 9.2 mu M). The pathological concentration of MGO (100 mu M) was then applied to investigate its effect on inducible nitric oxide synthase (iNOS) expression and NO release on interferon-gamma (IFN-gamma) (100 IU/ml) and lipopolysaccharide (LPS) (100 mu g/ml)-stimulated control ASMCs. MGO (100 mu M) inhibited IFN-gamma and LPS-stimulated iNOS expression through inhibiting Akt phosphorylation and inhibition of iNOS expression was prevented by L-arginine (100 mu M) co-treatment. These findings show for the first time that MGO inhibits IFN-gamma and LPS-stimulated iNOS expression in ASMCs, in addition to inhibiting IFN-gamma and LPS-induced Akt phosphorylation. The actions of MGO might contribute to the vascular dysfunction induced by MGO in diabetes.