Reactive Nitrogen Intermediates in Giant Cell Arteritis

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.

Phagocyte dysfunction in polymyalgia rheumatica and other age-related, chronic, inflammatory conditions

“…Nor did we find any difference in the patients with active PMR or EORA. However, it is possible that there are other aspects of monocyte function, such as NO production [54], as previously demonstrated in GCA lesions. Moreover, increased production of inflammatory cytokines by tissue macrophages and circulating monocytes has been shown in GCA and PMR [53,55].…”

Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia

“…24,25 Hence, decreased SOD bioactivity and increased myocardial nitrotyrosine immunoreactivity in our HC pigs reflect attenuated scavenging activity and increased abundance of superoxide anion associated with a pro-oxidant shift. Both increased formation of superoxide radical 26 and peroxynitrite 11,27 further impair SOD activity and thereby lead to a vicious cycle of increased oxidative stress. Notably, decreased Mn-SOD enzymatic bioactivity is not necessarily accompanied by decreased Mn-SOD protein expression, which can in fact be paradoxically increased.…”

Endothelial nitric oxide synthase gene polymorphisms in giant cell arteritis

“…Intima hyperplasia and inflammatory changes of the arterial wall are the main causes of luminal obstruction and tissue ischemia in GCA (26). The process of neocapillarization in GCA leads to the appearance of microvessels in the media and the hyperplastic intima (27), and eNOS is highly expressed on the endothelial cells lining these neovessels (28). NO derived from eNOS is critical for the regulation of leukocyte-endothelial cell interaction in these areas.…”