Insulin Coordinately Regulates Nitric Oxide Synthase and Argininosuccinate Synthase to Maintain Vascular Endothelial Function

Abstract

The pathogenesis of diabetes includes impairment of vascular endothelial cell nitric oxide (NO) production. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate‐limiting step of the citrulline nitric oxide cycle. First, using serum starved, cultured vascular endothelial cells, we show that insulin coordinately up‐regulates both eNOS and AS expression, supporting NO production. Second, using a rat model, we show that diminished eNOS and AS expression in rats with streptozotocin‐induced diabetes is reversed by insulin treatment, delivered via slow release pellets. Impaired endothelium‐dependent vasorelaxation is also reversed with insulin treatment. Thus, insulin supports endothelial function not only through regulation of eNOS, but also through the coordinate regulation of AS. (Supported by the James and Esther King Biomedical Research Program, DOH Florida; NIH RO1 HL083153‐01A2).