Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase
- 1 November 2007
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 293 (5), H2878-H2887
- https://doi.org/10.1152/ajpheart.01144.2006
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 (BH4). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH4becomes 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 BH4were 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 BH4oxidation 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 BH4oxidation in a tissue-selective manner. Since BH4oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions.Keywords
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