Relationship between iNOS expression and aortic cell proliferation and apoptosis in an elastase-induced model of aorta aneurysm and the effect of 1400 W administration.
BACKGROUND
In the present study, we employed an elastase infusion-dependent abdominal aortic aneurysm (AAA) model to examine inducible nitric oxide synthase (iNOS) expression in relation to cellular proliferation and apoptosis in this pathologic condition. Furthermore, we employed N-(3-(aminomethyl)benzyl)acetamidine (1400 W), a previously shown selective iNOS inhibitor, to further explore this relationship.


METHODS
Adult male Wistar rats were randomized into separate groups. Group A served as a control and received an intra-aortic saline infusion, while groups B, C, and D received an intra-aortic elastase infusion according to standard protocols. The animals in group C were administered postoperatively the highly selective iNOS inhibitor, 1400 W, while rats in group D received regularly the same compound preoperatively and postoperatively. The animals were killed at postoperative days 7 and 14. Aorta diameter and nitric oxide (NO), nitrite/nitrate, and MDA levels were measured. iNOS expression was assessed by immunohistochemistry and Western blot analysis, while Ki-67 immunohistochemistry and TUNEL assay were used to evaluate cellular proliferation and apoptosis, respectively.


RESULTS
Increased iNOS and NO levels accompanied aneurysm development in groups B, C, and D, but these levels were significantly lower in groups C and D, compared with group B. Interestingly, very low but detectable levels of iNOS were found in the control group, indicating a basal constitutive level. Cell growth parameters were augmented in group B compared with group A. In contrast, groups C and D exhibited a significant decrease of the cellular growth parameters but did not attain normal values.


CONCLUSIONS
iNOS-derived NO is associated with the cellular growth parameters of the vessel cells, predominantly smooth muscle cells. Selective iNOS blockage ameliorates the cellular remodeling in AAAs.
Sigala
F
F
1st Department of Surgery, Laiko Hospital, University of Athens Medical School, Athens, Greece.
Papalambros
E
E
Kotsinas
A
A
Andreadou
I
I
Sigalas
P
P
Kremastinos
D
D
Bastounis
E
E
Gorgoulis
V G
VG
D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D017209:Apoptosis; D002455:Cell Division; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007097:Imines / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D010196:Pancreatic Elastase; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D007097:Imines; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D009566:Nitrates; D009573:Nitrites; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010196:Pancreatic Elastase