Stimulation of Tetrahydrobiopterin Synthesis by Cyclosporin A during Lipopolysaccharide Treatment in Vascular Endothelial Cells

Abstract

We examined the effect of immunosuppressant cyclosporin A (CsA) on the synthesis of tetrahydrobiopterin (BH4), which is a cofactor for nitric oxide synthase (NOS), during treatment with lipopolysaccharide (LPS) in mouse brain microvascular endothelial cells. Addition of LPS to the endothelial cells increased the BH4 content and the mRNA level of GTP-cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH4 synthesis, and the LPSínduced increases in both the BH4 content and expression of GTPCH mRNA were further stimulated by the cotreatment with CsA. 2,4-Diamino-6-hydroxypyrimidine, an inhibitor of GTPCH, blocked the increase in BH4 content induced by CsA during the LPS treatment. Moreover. CsA stimulated the expression of inducible NOS (iNOS) mRNA during the LPS treatment. These findings suggest that CsA stimulates LPS-induced BH4 synthesis through the induction of GTPCH, and iNOS expression. CsA may increase NO production during LPS treatment in brain microvascular endothelial cells.

Keywords

• cyclosporin a
• tetrahydrobiopterin
• gtp-cyclohydrolase i
• lipopolysaccharide
• mouse brain microvascular endothelial cells