Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension

Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become “uncoupled,” producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate–salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47phox and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and…

• UD
  U.S. Department of Veterans Affairs
• AV
  Alexander von Humboldt-Stiftung
• DG
  Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
• NI
  National Institutes of Health

  Awards: HL58000, DK50740