Reactive nitrogen intermediates in giant cell arteritis: Selective nitration of neocapillaries

Astrid Borkowski, Brian R. Younge, Luke Szweda, Bettina Mock, Johannes Björnsson, Kerstin Moeller, Jörg J. Goronzy, Cornelia M. Weyand

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28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)115-123
Number of pages9
JournalAmerican Journal of Pathology
Volume161
Issue number1
DOIs
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Borkowski, A., Younge, B. R., Szweda, L., Mock, B., Björnsson, J., Moeller, K., Goronzy, J. J., & Weyand, C. M. (2002). Reactive nitrogen intermediates in giant cell arteritis: Selective nitration of neocapillaries. American Journal of Pathology, 161(1), 115-123. https://doi.org/10.1016/S0002-9440(10)64163-6