Experimental Abdominal Aortic Aneurysms in Mice Lacking Expression of Inducible Nitric Oxide Synthase

Lee, Jason K.; Borhani, Martin; Ennis, Terri L.; Upchurch, Gilbert R.; Thompson, Robert W.

doi:10.1161/hq0901.095750

Cited by 63 publications

(58 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lee et al demonstrated no protection from experimental AAA formation in male inducible nitric oxide synthase (iNOS Ϫ/Ϫ ) knockout mice, whereas female iNOS Ϫ/Ϫ mice had enhanced aortic expansion. 31 Although this study did not evaluate MMPs, it did suggest a gender-related effect of nitric oxide on experimental AAA formation.…”

Section: Discussionmentioning

confidence: 85%

Gender Differences in Experimental Aortic Aneurysm Formation

Ailawadi

Eliason

Roelofs

et al. 2004

ATVB

Self Cite

168

147

View full text Add to dashboard Cite

Objective-It is hypothesized that a male predominance, similar to that in humans, persists in a rodent model of experimental abdominal aortic aneurysm (AAA) via alterations in matrix metalloproteinases (MMPs). Methods and Results-Group I experiments were as follows: elastase perfusion of the infrarenal aorta was performed in male (M) and female (F) rats. At 14 days, aortas were harvested for immunohistochemistry, real-time polymerase chain reaction (PCR), and zymography. Group II experiments were the following: abdominal aorta was transplanted from F or M donors into F or M recipients. At 14 days, rodents that had undergone transplantation underwent elastase perfusion. In group III, male rats were given estradiol or sham 5 days before elastase perfusion. In group I, M rats had larger AAAs with higher frequency than did F rats. M rat aortas had more significant macrophage infiltrates and increased matrix metalloproteinase (MMP)-9 production and activity. In group II, M-to-M aortic transplants uniformly developed aneurysms after elastase perfusion, whereas F-to-F aortic transplants remained resistant to aneurysm formation. F aortas transplanted into M recipients, however, lost aneurysm resistance. In group III, estradiol-treated rats demonstrated smaller aneurysms and less macrophage infiltrate and MMP-9 compared with M controls after elastase. Conclusions-These data provide evidence of gender-related differences in AAA development, which may reflect an estrogen-mediated reduction in macrophage MMP-9 production.

show abstract

Section: Discussionmentioning

confidence: 85%

Gender Differences in Experimental Aortic Aneurysm Formation

Ailawadi

Eliason

Roelofs

et al. 2004

ATVB

Self Cite

168

147

View full text Add to dashboard Cite

show abstract

“…38 Estrogen mainly through ESR1 activates NOS2 and endothelial NOS (NOS3) pathways, reduces the oxidative stress of AAA, decreases MMP2 and MMP9, and exerts vasodilatory effects via nitric oxide. 61,65,82 Changes in gene activation of NOS3 and collagen via ESR1 and ESR2 in the media reduce the response of blood vessels to injury. 66 In addition, the antiapoptotic mechanisms of estrogens and the interaction with the fibrinolytic system through an increase of Serpine1 may prevent the destruction of the aortic wall.…”

Section: Discussionmentioning

confidence: 99%

“…Oophorectomized Nos2 À/À female mice showed a decreased incidence and diameter of AAA compared with noncastrated Nos2 À/À females, suggesting that the lack of estrogen reverses the accelerated AAA development and emphasizes the close interaction between estrogen and cellular NOS. 61 Another study did not find a difference in the aneurysm size or the number of macrophages between ovariectomized female rats and the control group, suggesting that persistent circulating estrogen or estrogen receptors can provide continued protection against AAA formation. In addition, they demonstrated that exogenous estrogens have prominent protective effects, as castrated females treated with 17b-estradiol presented smaller AAAs and lower macrophage counts compared to only castrated females.…”

Section: The Effect Of Castration On Aaa Parametersmentioning

confidence: 98%

“…More recently, sex differences in AAA have been studied in different animal models, which include the intraluminal infusion of elastase in rats 57 or mice, 58 angiotensin II (AngII) infusion in mice deficient in apolipoprotein E (Apoe À/À ), 59 and direct application of elastase at the anterior wall of the abdominal aorta in mice (Table III). 60 In 2001, Lee et al 61 described an increased incidence of AAA in female mice deficient in the inducible form of nitric oxide synthase (Nos2 À/À ) compared with male mice (80% vs. 40%), suggesting that the interaction between estrogen and cellular NOS could influence nitric oxide production and that the absence of NOS2 might have enhanced local MMP9 activity and promoted aneurysmal degeneration in a sex-specific manner. Another study reported a higher incidence and a larger size of AAA in male than in female mice in Apoe…”

Section: Sex Differences In Aaa Animal Models the Role Of Endogenous mentioning

confidence: 99%

See 1 more Smart Citation

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

Makrygiannis

Courtois

Drion

et al. 2014

Annals of Vascular Surgery

View full text Add to dashboard Cite

Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in men, whereas women have a greater risk of rupture and more frequently have concomitant thoracic aortic aneurysms. Moreover, women are diagnosed with AAA about 10 years later and seem to be protected by female sex hormones. In this MEDLINE-based review of literature, we examined human and animal in vivo and in vitro studies to further deepen our understanding of the sexual dimorphism of AAA. We focus on the role of sex hormones during the formation and growth of AAA. Endogenous estrogens and exogenous 17b-estradiol were found to exert favorable actions protecting from AAA in animal models, whereas exogenous hormone replacement therapy in humans had inconclusive results. Androgens, known to have detrimental effects in the vasculature, in sufficient levels maintain the integrity of the aortic wall through their anabolic actions and act differentially in men and women, whereas lower levels of testosterone have been associated with AAA in humans. In conclusion, sex differences remain an important area of AAA research, but further studies especially in humans are needed. Furthermore, differential molecular mechanisms of sex hormones constitute a potential therapeutic target for AAA.

show abstract

“…Similarly to our findings, elastase-induced aneurismal dilatation of the aorta is not reduced in iNOS À/À mice, even though accumulation of 3-nitrotyrosine is greatly reduced. 32 Pulmonary emphysema and aortic aneurysms may be closely related diseases from a pathophysiological standpoint.…”

Section: Discussionmentioning

confidence: 99%

Role of nitric oxide synthases in elastase-induced emphysema

Boyer

Plantier

Dagouassat

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

Nitric oxide (NO) in combination with superoxide produces peroxynitrites and induces protein nitration, which participates in a number of chronic degenerative diseases. NO is produced at high levels in the human emphysematous lung, but its role in this disease is unknown. The aim of this study was to determine whether the NO synthases contribute to the development of elastase-induced emphysema in mice. nNOS, iNOS, and eNOS were quantified and immunolocalized in the lung after a tracheal instillation of elastase in mice. To determine whether eNOS or iNOS had a role in the development of emphysema, mice bearing a germline deletion of the eNOS and iNOS genes and mice treated with a pharmacological iNOS inhibitor were exposed to elastase. Protein nitration was determined by immunofluorescence, protein oxidation was determined by ELISA. Inflammation and MMP activity were quantified by cell counts, RT-PCR and zymography in bronchoalveolar lavage fluid. Cell proliferation was determined by Ki67 immunostaining. Emphysema was quantified morphometrically. iNOS and eNOS were diffusely upregulated in the lung of elastase-treated mice and a 12-fold increase in the number of 3-nitrotyrosine-expressing cells was observed. Over 80% of these cells were alveolar type 2 cells. In elastaseinstilled mice, iNOS inactivation reduced protein nitration and increased protein oxidation but had no effect on inflammation, MMP activity, cell proliferation or the subsequent development of emphysema. eNOS inactivation had no effect. In conclusion, in the elastase-injured lung, iNOS mediates protein nitration in alveolar type 2 cells and alleviates oxidative injury. Neither eNOS nor iNOS are required for the development of elastase-induced emphysema.

show abstract

Experimental Abdominal Aortic Aneurysms in Mice Lacking Expression of Inducible Nitric Oxide Synthase

Cited by 63 publications

References 71 publications

Gender Differences in Experimental Aortic Aneurysm Formation

Gender Differences in Experimental Aortic Aneurysm Formation

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

Role of nitric oxide synthases in elastase-induced emphysema

Contact Info

Product

Resources

About