title: Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase.
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(4)). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH(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(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(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(4) oxidation in a tissue-selective manner. Since BH(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.
authors.affiliation: Center of Vascular Biology, Department of Pathology, Weill Medical College of Cornell University, New York, NY 10021, USA. rupmacis@med.cornell.edu
authors.forename: Rita K
authors.initials: RK
authors.lastname: Upmacis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Crabtree
authors.forename: Ruba S
authors.initials: RS
authors.lastname: Deeb
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
authors.forename: Paul B
authors.initials: PB
authors.lastname: Lane
authors.forename: Lea Esther S
authors.initials: LE
authors.lastname: Benguigui
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: David P
authors.initials: DP
authors.lastname: Hajjar
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism*; D001708:Biopterins / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009574:Nitro Compounds / Q000378:metabolism; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D004041:Dietary Fats; D009574:Nitro Compounds; D011506:Proteins; D001708:Biopterins; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II