title: Reactive nitrogen intermediates in giant cell arteritis: selective nitration of neocapillaries.
abstract: Arterial wall damage in giant cell arteritis (GCA) is mediated by several different macrophage effector functions, including the production of metalloproteinases and lipid peroxidation. Tissue-invading macrophages also express nitric oxide synthase (NOS)-2, but it is not known whether nitric oxide-related mechanisms contribute to the disease process. Nitric oxide can form nitrating agents, including peroxynitrite, a nitric oxide congener formed in the presence of reactive oxygen intermediates. Protein nitration selectively targets tyrosine residues and can result in a gain, as well as a loss, of protein function. Nitrated tyrosine residues in GCA arteries were detected almost exclusively on endothelial cells of newly formed microcapillaries in the media, whereas microvessels in the adventitia and the intima were spared. Nitration correlated with endothelial NOS-3 expression and not with NOS-2-producing macrophages, which preferentially homed to the hyperplastic intima. The restriction of nitration to the media coincided with the production of reactive oxygen intermediates as demonstrated by the presence of the toxic aldehyde, 4-hydroxynonenal. Depletion of tissue-infiltrating macrophages in human temporal artery-SCID mouse chimeras disrupted nitrotyrosine generation, demonstrating a critical role of macrophages in the nitration process that targeted medial microvessels. Thus, protein nitration in GCA is highly compartmentalized, reflecting the production of reactive oxygen and reactive nitrogen intermediates in the inflamed arterial wall. Heterogeneity of microvessels in NOS-3 regulation may be an additional determinant contributing to this compartmentalization and could explain the preferential targeting of newly generated capillary beds.
authors.affiliation: Department of Medicine and Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Borkowski
authors.forename: Brian R
authors.initials: BR
authors.lastname: Younge
authors.forename: Luke
authors.initials: L
authors.lastname: Szweda
authors.forename: Bettina
authors.initials: B
authors.lastname: Mock
authors.forename: Johannes
authors.initials: J
authors.lastname: Björnsson
authors.forename: Kerstin
authors.initials: K
authors.lastname: Moeller
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D002678:Chimera; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D013700:Giant Cell Arteritis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism; D017540:Tunica Media / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D009566:Nitrates; D026361:Reactive Nitrogen Species; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse