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Accumulation of protein 3-nitrotyrosine (3-NT) and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH4), occur during the pathogenesis of atherosclerosis. This study sought to quantify 3-NT accumulation and BH4 oxidation in organs of ApoE-/- atherogenic mice, and also determine the specific contribution of inducible NOS (iNOS) to these processes. Although protein 3-NT accumulation and BH4 oxidation were low or undetected in the heart, lung, liver and kidney of 3-week old ApoE-/- mice, robust accumulation was evident after 24 weeks on an atherogenic diet. Since 3-NT accumulation was diminished in the heart, lung and liver of ApoE-/-iNOS-/- mice, iNOS-derived species are involved in this reaction, iNOS deletion also protected against BH4 oxidation in the heart, lung and kidney of atherogenic ApoE-/- mice, but not the brain or liver. These findings demonstrate that iNOS-derived species are increased in atherosclerotic ApoE-/- mice and contribute differentially to protein nitration and BH4 oxidation. Since BH4 oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions. [ABSTRACT FROM AUTHOR]