Abstract
Diminished nitric oxide (NO) bioactivity and enhanced peroxynitrite formation have been implicated as major contributors to atherosclerotic vascular dysfunctions. Hallmark reactions of peroxynitrite include the accumulation of 3-nitrotyrosine (3-NT) in proteins and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH^sub 4^). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH^sub 4^ becomes oxidized in organs of apolipoprotein E-deficient (ApoE...) atherosclerotic mice and 2) determine the specific contribution of inducible NOS (iNOS) to these processes. Whereas protein 3-NT and oxidized BH^sub 4^ were undetected or near the detection limit in heart, lung, and kidney of 3-wk-old ApoE... mice or ApoE... mice fed a regular chow diet for 24 wk, robust accumulation was evident after 24 wk on a Western (atherogenic) diet. Since 3-NT accumulation was diminished 3- to 20-fold in heart, lung, and liver in ApoE... mice missing iNOS, iNOS-derived species are involved in this reaction. In contrast, iNOS-derived species did not contribute to elevated protein 3-NT formation in kidney or brain. iNOS deletion also afforded marked protection against BH^sub 4^ oxidation in heart, lung, and kidney of atherogenic ApoE... mice but not in brain or liver. These findings demonstrate that iNOS-derived species are increased during atherogenesis in ApoE... mice and that these species differentially contribute to protein 3-NT accumulation and BH^sub 4^ oxidation in a tissue-selective manner. Since BH^sub 4^ oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions. (ProQuest: ... denotes formulae/symbols omitted.)