Deficiency in Inducible Nitric Oxide Synthase Results in Reduced Atherosclerosis in Apolipoprotein E-Deficient Mice

Detmers, Patricia A.; Hernandez, Melba; Mudgett, John S.; Hassing, Heide; Burton, Charlotte; Mundt, Steven S.; Chun, Sam; Fletcher, Daniel S.; Card, Deborah; Lisnock, JeanMarie; Weikel, Reneé; Bergstrom, James D.; Shevell, Diane E.; Hermanowski‐Vosatka, Anne; Sparrow, Carl P.; Chao, Yu‐Sheng; Rader, Daniel J.; Wright, Samuel D.; Puré, Ellen

doi:10.4049/jimmunol.165.6.3430

Cited by 191 publications

(136 citation statements)

References 45 publications

Supporting

Mentioning

132

Contrasting

Order By: Relevance

“…A more recent report confirms our results that iNOS deficiency reduces atherosclerosis in apoE-KO mice. 33 Our study differs, however, because we assayed en face lesion area as opposed to aortic root lesions, we used animals that were all backcrossed to the C57BL6 strain, and we provide data about levels of plasma MDA-TBA adducts.…”

Section: Discussionmentioning

confidence: 99%

Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice

et al. 2001

View full text Add to dashboard Cite

Background-Inducible nitric oxide synthase (iNOS) is expressed by leukocytes and smooth muscle cells in atherosclerotic lesions. To test whether NO produced by iNOS deficiency affects atherosclerosis, we studied apoE/iNOS-double knockout (dKO) and apoE-knockout (KO) control animals fed a "Western-type" diet. Methods and Results-After 16 weeks of Western-type diet, the aortic lesion area in apoE/iNOS-dKO males and females was significantly reduced, by 22% and 21%, respectively, compared with apoE-KO males and females. This effect was more pronounced after 24 weeks of Western-type diet, after which lesion formation in male and female dKO mice was reduced by 38% and 40%, respectively. Plasma levels of lipoperoxides in apoE/iNOS-dKO mice (2.0Ϯ0.23 mol/L) were significantly lower than in apoE-KO control animals (3.2Ϯ0.44 mol/L; Pϭ0.02). To test whether substrate deficiency plays a role in the proatherogenic actions of iNOS, we administered L-arginine to apoE-KO animals for 16 and 24 weeks. L-Arginine treatment did not affect lesion formation in apoE-KO animals fed a Western-type diet. Conclusions-Genetic deficiency of iNOS decreases diet-induced atherosclerosis and lowers plasma levels of lipoperoxides, a marker for oxidative stress, in apoE-KO animals. Reduction in iNOS-mediated oxidative stress could partly explain protection from lesion formation in dKO animals.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice

et al. 2001

View full text Add to dashboard Cite

show abstract

“…Macrophages also serve as the source of other inflammatory mediators contributing to the development of endometriosis, including NO. NO produced in abundance by the inducible form of NO synthase (iNOS, NOS2), induced by oxidant-sensitive transcription factors like NFkB, has the potential to exacerbate endometriosis by promoting inflammation and necrosis at the site of lesion (Beckman & Koppenol 1996, Detmers et al 2000. Moreover, the peritoneal accumulation of pro-oxidant and pro-inflammatory factors during retrograde menstruation, such as hemoglobin and its by-product heme, may cause OS-mediated mesothelial layer damage and chronic inflammation, permitting the attachment and development of endometrial fragments in the peritoneum.…”

Section: Iron-induced Peritoneal Os In Endometriosis Developmentmentioning

confidence: 99%

Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis

Pirdel¹,

Pirdel²

2014

Reproduction

View full text Add to dashboard Cite

This article presents an overview of the involvement of iron overload-induced nitric oxide (NO) overproduction in apoptosis of peritoneal macrophages of women with endometriosis. We have postulated that the peritoneal iron overload originated from retrograde menstruation or bleeding lesions in the ectopic endometrium, which may contribute to the development of endometriosis by a wide range of mechanisms, including oxidative damage and chronic inflammation. Excessive NO production may also be associated with impaired clearance of endometrial cells by macrophages, which promotes cell growth in the peritoneal cavity. Therefore, further research of the mechanisms and consequences of macrophage apoptosis in endometriosis helps discover novel therapeutic strategies that are designed to prevent progression of endometriosis.

show abstract

“…Analysis of transgenic mice that lack or overexpress NO synthases indicated that NO exerts both protective (4,5) and atherogenic (6)(7)(8)(9) effects. The double role of NO might explain why NO-generating drugs (e.g., glyceryl trinitrate) have not been reported to limit the progression of atherosclerosis in humans.…”

mentioning

confidence: 99%

A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells

Wolfsgruber¹,

Feil²,

Brummer³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Nitric oxide (NO) exerts both antiatherogenic and proatherogenic effects, but the cellular and molecular mechanisms that contribute to modulation of atherosclerosis by NO are not understood completely. The cGMP-dependent protein kinase I (cGKI) is a potential mediator of NO signaling in vascular smooth muscle cells (SMCs). Postnatal ablation of cGKI selectively in the SMCs of mice reduced atherosclerotic lesion area, demonstrating that smooth muscle cGKI promotes atherogenesis. Cell-fate mapping indicated that cGKI is involved in the development of SMC-derived plaque cells. Activation of endogenous cGKI in primary aortic SMCs resulted in cells with increased levels of proliferation; increased levels of vascular cell adhesion molecule-1, peroxisome proliferator-activated receptor ␥, and phosphatidylinositol 3-kinase͞Akt signaling; and decreased plasminogen activator inhibitor 1 mRNA, which all are potentially proatherogenic properties. Taken together, these results highlight the pathophysiologic significance of vascular SMCs in atherogenesis and identify a key role for cGKI in the development of atherogenic SMCs in vitro and in vivo. We suggest that activation of smooth muscle cGKI contributes to the proatherogenic effect of NO and that inhibition of cGKI might be a therapeutic option for treating atherosclerosis in humans.A therosclerosis causes heart attack and stroke, the major causes of death in industrial nations. The pathophysiology of atherogenesis is complex. It is considered to be a chronic inflammatory condition that results from the interaction between modified lipoproteins and various cell types, including leukocytes, platelets, and cells of the vessel wall (1). The development of an atherosclerotic plaque involves, in addition to inflammation, the phenotypic modulation of vascular smooth muscle cells (SMCs) to proliferating and dedifferentiated cells. However, the mechanisms that contribute to the development of plaque SMCs and their pathophysiologic significance are not well understood (2).The signaling molecule nitric oxide (NO) has critical roles in the pathogenesis of atherosclerosis (3). Analysis of transgenic mice that lack or overexpress NO synthases indicated that NO exerts both protective (4, 5) and atherogenic (6-9) effects. The double role of NO might explain why NO-generating drugs (e.g., glyceryl trinitrate) have not been reported to limit the progression of atherosclerosis in humans. The opposing actions of NO on atherogenesis might depend on the spatiotemporal profile of its production and are likely mediated by different cellular and molecular mechanisms. Signaling pathways in SMCs that contribute to NO modulation of atherogenesis have not been identified. In vascular SMCs, NO is thought to exert many of its effects by activation of soluble guanylyl cyclase, synthesis of the second messenger cGMP, and activation of cGMP-dependent protein kinase I (cGKI) (10). The analysis of the functional significance of cGKI in NO͞cGMP signaling is complicated by the existence of multiple receptors ...

show abstract

Deficiency in Inducible Nitric Oxide Synthase Results in Reduced Atherosclerosis in Apolipoprotein E-Deficient Mice

Cited by 191 publications

References 45 publications

Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice

Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice

Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis

A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells

Contact Info

Product

Resources

About