title: Tetrahydrobiopterin attenuates superoxide-induced reduction in nitric oxide.
abstract: 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.
authors.affiliation: Cardiovascular Research Institute and Department of Systems Biology and Translational Medicine, Texas A and M Health Science Center, Temple, TX 76504, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Bowers
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hargrove
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kelly
authors.forename: Guoyao
authors.initials: G
authors.lastname: Wu
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Meininger
mesh_terms: D000704:Analysis of Variance; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D015153:Blotting, Western; D042783:Endothelial Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D019255:NADPH Oxidases; C003402:sapropterin; D010100:Oxygen