In cultured rat smooth muscle cells, IL-1beta stimulated NO synthesis directly via iNOS expression and indirectly by upregulating DDAH and reducing the endogenous NO synthase inhibitor ADMA.
The ADMA-DDAH system regulates inflammation-mediated NO production in vascular smooth muscle cells by modulating iNOS activity.
p-value: p=<0.01
In response to vascular insults, inflammatory cytokines stimulate vascular smooth muscle cells (SMCs) to express an inducible isoform of nitric oxide synthase (iNOS). Asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, is metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To determine whether the ADMA-DDAH system regulates cytokine-induced NO production, cultured rat SMCs were exposed to interleukin-1beta (IL-1beta). IL-1beta (1 to 100 U/mL) dose-dependently stimulated not only iNOS but also DDAH expression and enzyme activity, accompanied by an increase in NO metabolite and by a decrease in ADMA content in culture media. A DDAH inhibitor (4124W, 5 mmol/L) augmented ADMA production (P<0.01) and decreased NO synthesis (P<0.01) in IL-1beta-stimulated SMCs. On the other hand, an adenovirus-mediated overexpression of DDAH reduced ADMA and enhanced NO production. Exogenous administration of NO donors (SNAP and SIN-1) dose-dependently increased NO metabolite in the culture media but had no effect on ADMA. Our results indicate two mechanisms of IL-1beta-induced NO synthesis: the direct stimulation of the expression of iNOS and the indirect stimulation of iNOS activity by upregulating DDAH and reducing ADMA. The ADMA-DDAH system may be another regulatory mechanism of inflammation-mediated NO production for human vascular diseases.
Ueda et al. (Thu,) reported a other. Interleukin-1beta (IL-1beta) was evaluated on Nitric oxide (NO) synthesis and ADMA production (p=<0.01). In cultured rat smooth muscle cells, IL-1beta stimulated NO synthesis directly via iNOS expression and indirectly by upregulating DDAH and reducing the endogenous NO synthase inhibitor ADMA.