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Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase

¹Center of Vascular Biology, ²Department of Pathology and Laboratory Medicine, and ³Department of Pharmacology, Weill Medical College of Cornell University, New York, New York; and ⁴Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina

Submitted 17 October 2006 ; accepted in final form 25 August 2007

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 (BH₄). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH₄ 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 BH₄ 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 BH₄ 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 BH₄ oxidation in a tissue-selective manner. 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.

inducible nitric oxide synthase; high-fat diet

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