Statin Increases GTP Cyclohydrolase I mRNA and 5,6,7,8-Tetrahydrobiopterin in Vascular Endothelial Cells

Abstract

We investigated the effects of HMG-CoA reductase inhibitors, so-called statins, on 5,6,7,8-tctrahydrobioptcrin (BH4) metabolism in human umbilical vein endothelial cells (HUVEC). The mRNA of GTP cyclohydrolase I (GTPCH), as well as cNOS, was upregulated in HUVEC treated with cerivastatin. This increase was time- and dose-dependent. Fluvastatin was also observed to enhance GTPCH and eNOS mRNA levels. In parallel with this observation, cerivastatin increased intracellular BH4. Cerivastatin increased the stability of eNOS mRNA. However, it did not alter the stability of GTPCH mRNA but increased GTPCH gene transcription as shown by nuclear run-on assays. Preteatment of HUVEC with the selective GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, caused a decrease in intracellular BH4 and decreased citrulline formation following stimulation with ionomycin. Furthermore, the potentiating effect of cerivasatin was decreased by limiting the cellular availability of BH4. In addition to augmenting eNOS expression, statins potentiate GTPCH gene expression and BH4 synthesis, thereby increasing NO production and preventing relative shortages of BH4

Keywords

• statin
• nitric oxide
• tetrahydrobiopterin
• endothelial cells