Mechanism of vasculitis and aneurysms in Kawasaki disease: role of nitric oxide.
NO in vivo has both beneficial and nonbeneficial effects depending on site and concentration. Peroxynitrite, resulting from the reaction of NO with superoxide radical, causes cellular damage. Nitrotyrosine, end product of NO's toxic effects on cellular proteins, is a stable compound that can be used to detect evidence of harmful quantities of NO. We sought to detect nitrotyrosine in coronary arterioles of DBA/2 mice injected intraperitoneally with Lactobacillus casei cell wall. The inflammatory response induced occurred in perivascular fashion and involved mainly macrophages. It was variable according to time points, being severe on days 10 and 14 and mild to moderate on days 3 and 7. Few basal inflammatory cells appeared in controls injected with phosphate-buffered saline. Western immunoblots of homogenized hearts on days 10 and 14 demonstrated specific nitrated proteins. Immunohistochemistry of frozen sections of diseased hearts showed positive immunoreactivity for nitrotyrosine in coronary arterioles at the same time points. These findings were absent in the controls. We also determined the expression of inducible nitric oxide synthase (iNOS) in controls on days 10 and 14. iNOS colocalized with nitrotyrosine in perivascular macrophages and coronary arterioles of treated mice. Additionally, aneurysms were found on day 10 and intracardiac hemorrhage with consequent death on day 14. These observations supply evidence that NO through its reactive product, peroxynitrite, and its antigen/tissue marker, nitrotyrosine, is directly involved in coronary arteritis and aneurysm development in mice models of Kawasaki disease (KD). This article shows that macrophages are central to this and bolsters the likelihood of L. casei being the cause of KD.
Adewuya
Oladapo
O
Department of Integrative Biology and Pharmacology, Houston Medical School, University of Texas, 6431 Fannin, Houston, TX 77030, USA. Oaadewuy@utmb.edu
Irie
Yasuyuki
Y
Bian
Ka
K
Onigu-Otite
Edore
E
Murad
Ferid
F
D000783:Aneurysm / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002473:Cell Wall / Q000276:immunology; D003331:Coronary Vessels / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D007780:Lacticaseibacillus casei / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D009080:Mucocutaneous Lymph Node Syndrome / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism; D013927:Thrombosis / Q000473:pathology; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014657:Vasculitis / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse