Hydrogen Peroxide Stimulates the LPS-induced Tetrahydrobiopterin Synthesis in Mouse Brain Microvascular Endothelial Cells

Abstract

Tetrahydrobiopterin (BH4) is one of the cofactors for nitric oxide synthase (NOS), and also has a protective effect against reactive oxygen species (ROS)- and/or nitric oxide (NO)-induced cytotoxicities. Lipopolysaccharide (LPS) induces NO production and BH4 synthesis, and also ROS release. This study examined whether hydrogen peroxide, one of the ROS, has a regulatory role in BH4 synthesis in vascular endothelial cells. Addition of LPS to the endothelial cells increased the BH4 content. Although the LPS-induced increase in BH4 content was not affected by the treatment with superoxide dismutase and catalase, co-treatment with hydrogen peroxide further stimulated the LPS-induced increase in BH4 content. Moreover, the hydrogen peroxide-induced increase in BH4 content in the presence of LPS was completely inhibited by the treatment with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I (GTPCH). These findings suggest that hydrogen peroxide may stimulate LPS-induced BH4 synthesis through the induction and/or activation of GTPCH. Under inflammation, hydrogen peroxide seems to stimulate BH4 synthesis.

Keywords

• hydrogen peroxide
• tetrahydrobiopterin
• endothelial cells
• rat
• lipopolysacharide