Mice lacking inducible nitric oxide synthase develop spontaneous hypercholesterolaemia and aortic atheromas

Ihrig, Melanie; Dangler, Charles A.; Fox, James G.

doi:10.1016/s0021-9150(00)00636-5

Cited by 47 publications

(25 citation statements)

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“…Although no atherosclerotic lesions were observed in the present study (data not shown), serum cholesterol levels were significantly higher in the iNOS Ϫ/Ϫ mice than in the WT controls (Table 2), a result which is consistent with our previous study (19). Elevated cholesterol levels were influenced by genotype (P Ͻ 0.0007; the levels for iNOS Ϫ/Ϫ mice were higher than those for WT mice) and gender (P Ͻ 0.002; the levels for males were higher than those for females).…”

Section: Evaluation Of Serum Antibody Responses To H Felissupporting

confidence: 94%

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GastricHelicobacterInfection Induces a Th2 Phenotype but Does Not Elevate Serum Cholesterol in Mice Lacking Inducible Nitric Oxide Synthase

et al. 2005

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Persistent Helicobacter felis infection in (C57BL/6 ؋ 129SvEv)F 1 mice induces chronic gastritis. Expression of inducible nitric oxide synthase (iNOS) is upregulated in response to Helicobacter infection. In this study, 20 10-week-old iNOS ؊/؊ mice and 20 wild-type [(C57BL/6 ؋ 129SvEv)F 1 ] mice were infected with H. felis by oral gavage and were assessed histologically and serologically at 32 weeks postinfection. Equal numbers of uninfected controls were sham inoculated. The mice were scored for severity of gastric inflammation, hyperplasia, glandular atrophy, and mucous metaplasia in the corpus and for the level of helicobacter colonization. The immunoglobulin G1 (IgG1), IgG2a, and IgG2c antibody responses to H. felis were determined. As a secondary measure, serum cholesterol levels were assessed. iNOS ؊/؊ mice have a propensity for increased serum cholesterol, and although controversial, several human epidemiologic studies have demonstrated an association between Helicobacter infection and several risk factors for cardiovascular disease, including elevated serum cholesterol. Nevertheless, no differences in serum cholesterol levels were observed between the H. felis-infected and -uninfected iNOS ؊/؊ mice in this study. The uninfected animals had minimal to no gastric pathology. The gastric pathology scores for the infected animals were reduced significantly in the iNOS-deficient mice relative to those for the wild-type mice (all P < 0.01). Helicobacter-infected iNOS ؊/؊ mice had chronic lymphoid infiltration and negligible to mild glandular atrophy and mucous metaplasia in the fundic mucosa, while H. felis-infected wild-type mice had severe atrophic and metaplastic mucosal changes. The atrophic gastritis in the infected wild-type mice, particularly the female mice, was also accompanied by greater granulocytic infiltration, antral hyperplasia, and diminished antral colonization, unlike that in the infected iNOS ؊/؊ mice. iNOS

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Section: Evaluation Of Serum Antibody Responses To H Felissupporting

confidence: 94%

“…A prior study from this laboratory demonstrated that iNOS-deficient (iNOS Ϫ/Ϫ ) mice have elevated serum cholesterol levels and concomitant atherosclerotic lesions when they are fed a basal synthetic diet (19).…”

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confidence: 99%

GastricHelicobacterInfection Induces a Th2 Phenotype but Does Not Elevate Serum Cholesterol in Mice Lacking Inducible Nitric Oxide Synthase

et al. 2005

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“…13 Ihrig et al reported that blood pressure was significantly higher in iNOS-deficient mice than in WT on a high-salt diet. 41 These data suggest that NO produced by iNOS plays an important role in preventing salt-sensitive hypertension. However, results have been controversial.…”

Section: Sun Et Al Role Of Inos In Doca-salt Hypertension 1359mentioning

confidence: 90%

Lack of Inducible NO Synthase Reduces Oxidative Stress and Enhances Cardiac Response to Isoproterenol in Mice With Deoxycorticosterone Acetate–Salt Hypertension

et al. 2005

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Abstract-Although NO derived from endothelial NO synthase (eNOS) is thought to be cardioprotective, the role of inducible NO synthase (iNOS) remains controversial. Using mice lacking iNOS (iNOSϪ/Ϫ), we studied (1) whether development of hypertension, cardiac hypertrophy, and dysfunction after deoxycorticosterone acetate (DOCA)-salt would be less severe compared with wild-type controls (WT; C57BL/6J), and (2) whether the cardioprotection attributable to lack of iNOS is mediated by reduced oxidative stress. Mice were uninephrectomized and received either DOCA-salt (30 mg/mouse SC and 1% NaClϩ0.2% KCl in drinking water) or vehicle (tap water) for 12 weeks. Systolic blood pressure (SBP) was measured weekly. Left ventricular (LV) ejection fraction (EF) by echocardiography and cardiac response to isoproterenol (50 ng/mouse IV) were studied at the end of the experiment. Expression of eNOS and iNOS as well as the oxidative stress markers 4-hydroxy-2-nonenal (4-HNE, a marker of lipid peroxidation) and nitrotyrosine (a marker for peroxynitrite) were determined by Western blot and immunohistochemical staining, respectively. DOCA-salt increased SBP and LV weight similarly in both strains and decreased EF in WT but not in iNOSϪ/Ϫ. Cardiac contractile and relaxation responses to isoproterenol were greater, 4-HNE and nitrotyrosine levels were lower, and eNOS expression tended to be higher in iNOSϪ/Ϫ. We conclude that lack of iNOS leads to better preservation of cardiac function, which may be mediated by reduced oxidative stress and increased eNOS; however, it does not seem to play a significant role in preventing DOCA-salt-induced hypertension and hypertrophy. Key Words: nitric oxide synthase Ⅲ cardiac function Ⅲ oxidative stress N itric oxide is synthesized from L-arginine by 3 isoforms of NO synthase (NOS), described as neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). In the heart, eNOS and nNOS are constitutively expressed in the endocardium, vascular endothelium, and cardiomyocytes, and help regulate vascular tone and cardiac contraction. [1][2][3] In contrast, iNOS is induced in the myocardium in response to various stimuli such as inflammatory mediators, cytokines, and growth factors as well as hypoxia and ischemia, 4,5 and its expression correlates positively with the severity of cardiac dysfunction and cytokine expression. 6,7 Induction and/or activation of iNOS will produce larger amounts of NO, which reacts with superoxide (O 2 Ϫ ) to form the highly cytotoxic oxidant peroxynitrite (ONOO Ϫ ). Recently, it has been demonstrated that iNOS is also capable of producing O 2 Ϫ , which is transformed to hydrogen peroxide (H 2 O 2 ) either spontaneously or via an enzymatic reaction with superoxide dismutase. 8,9 Both ONOO Ϫ and H 2 O 2 have been implicated in tissue injury and organ dysfunction, including the heart. 10 -12 The role of iNOS in the pathophysiology of hypertension and cardiac hypertrophy remains controversial. A number of studies have shown that iNOS expression and activity are altered in hypertens...

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“…Despite these findings, however, the contribution of nitric oxide deficiency to vascular disease has been controversial. Kuhlencordt et al (23) reported that iNOS deficiency in mice resulted in decreased lipid peroxides and decreased lesion size in an atherosclerosis model, whereas Ihrig, Dangler, and Fox (24) reported that iNOS deficiency resulted in increased cholesterol levels and an increased lesion incidence. In the context of injury-induced hyperplasia, Chyu et al (25) reported that iNOS ablation resulted in a decrease of neointimal hyperplasia, but Koglin et al (26) concluded from their study in a vascular allograft model that iNOS deficiency resulted in increased neointimal hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase

Moore

Hui

2005

Journal of Lipid Research

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Previous studies have shown apolipoprotein E (apoE) recruitment to medial layers of carotid arteries after vascular injury in vivo and apoE activation of inducible nitric oxide synthase (iNOS) in smooth muscle cells in vitro.This investigation explored the relationship between medial apoE recruitment and iNOS activation in protection against neointimal hyperplasia. ApoE was present in both neointimalresistant C57BL/6 mice and neointimal-susceptible FVB/N mice 24 h after carotid denudation, but iNOS expression was observed only in the neointimal-resistant C57BL/6 mice. However, iNOS was not observed in apoE-defective C57BL/6 mice. In contrast, overexpression of apoE in FVB/N mice activated iNOS expression in the injured vessels, resulting in protection against neointimal hyperplasia. ApoE and iNOS were colocalized in the medial layer of neointimalresistant mouse strains. Endothelial denudation of carotid arteries in the iNOS-deficient NOS2 ؊ / ؊ mice did not increase neointimal hyperplasia but significantly increased medial thickness and area. The iNOS-specific inhibitor also abrogated the apoE protective effects on vascular response to injury in apoE-overexpressing FVB/N mice. Thus, injuryinduced activation of iNOS requires apoE recruitment. Moreover, both apoE and iNOS are necessary for the suppression of cell proliferation, and apoE recruitment without iNOS expression resulted in medial hyperplasia without cell migration to the intima. Neointimal hyperplasia is a critical pathological process in several vascular occlusive diseases, including atherosclerosis, vein graft-induced arteriosclerosis, and the restenotic response to angioplasty and stent placement (1-4). The key cause of its pathology is endothelial damage, which exposes the underlying smooth muscle cells in the media to cytokines, growth factors, and other plasma components in the circulation, resulting in a loss of contractile characteristics and adoption of a synthetic phenotype (5, 6). Phenotypic activation of the underlying smooth muscle cells results in their migration from the media to the intima, where their proliferation and increased synthetic potential lead to the formation of the occlusive neointima (7).Recent studies in mice have shown that one determinant regulating the severity of neointimal formation is the level of apolipoprotein E (apoE) in the circulation. Results of these studies showed that transgenic overexpression of apoE is protective and that apoE gene ablation exacerbates neointimal hyperplasia caused by mechanically induced endothelial denudation (8). In fact, subphysiological levels of apoE were shown to have beneficial effects in limiting neointimal hyperplasia without correcting for hypercholesterolemia in apoE-null mice (9). The protective role of apoE has been established to involve the recruitment of circulating apoE to the medial layers of the injured vessel (10). It is likely that apoE interaction with the medial smooth muscle cells limits their migration and proliferation in response to growth factors prese...

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Mice lacking inducible nitric oxide synthase develop spontaneous hypercholesterolaemia and aortic atheromas

Cited by 47 publications

References 18 publications

GastricHelicobacterInfection Induces a Th2 Phenotype but Does Not Elevate Serum Cholesterol in Mice Lacking Inducible Nitric Oxide Synthase

GastricHelicobacterInfection Induces a Th2 Phenotype but Does Not Elevate Serum Cholesterol in Mice Lacking Inducible Nitric Oxide Synthase

Lack of Inducible NO Synthase Reduces Oxidative Stress and Enhances Cardiac Response to Isoproterenol in Mice With Deoxycorticosterone Acetate–Salt Hypertension

Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase

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