Experimental abdominal aortic aneurysms in mice lacking expression of inducible nitric oxide synthase.
To determine if nitric oxide synthase (NOS) contributes to the pathophysiology of abdominal aortic aneurysms (AAAs), C57BL/6J mice underwent transient aortic injury to induce a chronic inflammatory response. Wild-type mice developed a significant increase in aortic diameter within 14 days of elastase perfusion (115+/-16%, 40% incidence of AAAs), along with intense and widespread staining for nitrotyrosine, mononuclear inflammation, and delayed destruction of the elastic lamellae. Expression of both endothelial and neuronal forms of NOS was substantially decreased within AAAs, whereas inducible NOS (iNOS) mRNA was increased 360%, and the enzyme was localized to infiltrating inflammatory cells. By using mice with targeted deletion of iNOS to evaluate the functional importance of this enzyme, male iNOS(-/-) mice developed the same extent of aneurysmal dilatation as congenic controls (121+/-22%, 40% incidence of AAAs) and exhibited similar structural features except for diminished nitrotyrosine staining. Aneurysmal dilatation was actually enhanced in female iNOS(-/-) mice (141+/-16%, 80% incidence of AAAs; P<0.05), but this effect was reversed by previous oophorectomy. Although extensive protein nitration and increased expression of iNOS accompany the development of elastase-induced experimental AAAs, iNOS is not required in this process and its absence may be deleterious.
Lee
J K
JK
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, MO, USA.
Borhani
M
M
Ennis
T L
TL
Upchurch
G R
GR
Thompson
R W
RW
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004108:Dilatation, Pathologic; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D010052:Ovariectomy; D010196:Pancreatic Elastase; D012333:RNA, Messenger / Q000096:biosynthesis; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D012333:RNA, Messenger; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010196:Pancreatic Elastase