Hyperglycemia stimulates vascular arginase activity

Abstract

Arginase is the central enzyme in the hepatic urea cycle, metabolizing L-arginine to L-ornithine and urea. We recently discovered that vascular cells also express arginase activity and that arginase competes with nitric oxide synthase for L-arginine and promotes endothelial and smooth muscle dysfunction. Since diabetes is associated with vascular cell dysfunction, the present study examined whether hyperglycemia regulates arginase activity in vascular cells. Treatment of cultured vascular smooth muscle or endothelial cells with glucose (5-30 mM) stimulated arginase activity in a concentration- and time-dependent manner. A significant increase in vascular cell arginase activity was first noted 4 hours after glucose exposure and arginase activity progressively increased during 24 hours of treatment. In addition, glucose potentiated the induction of vascular arginase activity by growth factors and inflammatory cytokines. The glucose-mediated elevation in vascular arginase activity was associated with an increase in arginase I protein and mRNA. Finally, streptozotocin-induced diabetic rats exhibited a significant increase in plasma glucose levels (352±52 vs 155±15 mg/dL in control animals) that was associated an approximate 50% increase in vascular arginase activity. In conclusion, the present study demonstrates that hyperglycemia stimulates vascular arginase activity by inducing the expression of arginase I. The ability of hyperglycemia to stimulate arginase activity may contribute to vascular dysfunction and promote the development of vascular disease in type I diabetes. Supported by the Juvenile Diabetes Research Foundation International and the National Institutes of Health.