Tetrahydrobiopterin attenuates superoxide-induced reduction in nitric oxide.
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NADPH oxidase, a source of superoxide anion (·O2(-)), can be stimulated by oxidized low-density lipoprotein (OxLDL). We examined whether tetrahydrobiopterin (BH4) could reduce OxLDL-induced ·O2(-) production by NADPH oxidase, increasing nitric oxide (NO) synthesis. Endothelial cells incubated with OxLDL produced more ·O2(-) (35-67%) than untreated cells, with the highest increase 1 hour after OxLDL addition. The elevated ·O2(-) production correlated with the translocation of the p47phox subunit of NADPH oxidase from the cytosol to the membrane. Cells exhibited a marked decrease in both BH4 (83 per cent) and NO (54 per cent) in the same hour following exposure to OxLDL. An NADPH oxidase inhibitor, apocynin, or antioxidant, N-acetyl-L-cysteine, substantially attenuated the reduction in both BH4 and NO. The ·O2(-) production was increased when cells were pretreated with an inhibitor of BH4 synthesis and decreased following pretreatment with a BH4 precursor, suggesting that NADPH oxidase-induced imbalance of endothelial NO and ·O2(-) production can be modulated by BH4 concentrations. BH4 may be critical in combating oxidative stress, restoring proper redox state, and reducing risk for cardiovascular disease including atherosclerosis.
author list (cited authors)
Bowers, M. C., Hargrove, L. A., Kelly, K. A., Wu, G., & Meininger, C. J.