Tetrahydrobiopterin attenuates superoxide-induced reduction in nitric oxide

Front Biosci (Schol Ed). 2011 Jun 1;3:1263-72. doi: 10.2741/s224.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Biopterin / analogs & derivatives*
  • Biopterin / metabolism
  • Blotting, Western
  • Endothelial Cells
  • Humans
  • Lipoproteins, LDL / metabolism*
  • NADPH Oxidases / metabolism*
  • Nitric Oxide / biosynthesis*
  • Oxidation-Reduction
  • Oxygen / metabolism*
  • Superoxides / metabolism


  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Superoxides
  • Biopterin
  • Nitric Oxide
  • NADPH Oxidases
  • sapropterin
  • Oxygen